식물의 2차대사산물(테르페노이드, 알칼로이드, 페놀화합물).. 약물의 25% 차지

[문형철]

Molecules

. 2022 Jan 5;27(1):313. doi: 10.3390/molecules27010313

Plant Secondary Metabolites Produced in Response to Abiotic Stresses Has Potential Application in Pharmaceutical Product Development

Karma Yeshi 1,*, Darren Crayn 2, Edita Ritmejerytė 1, Phurpa Wangchuk 1

Editor: Manuel Simões

• Author information
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PMCID: PMC8746929  PMID: 35011546

Abstract

Plant secondary metabolites (PSMs) are vital for human health and constitute the skeletal framework of many pharmaceutical drugs. Indeed, more than 25% of the existing drugs belong to PSMs. One of the continuing challenges for drug discovery and pharmaceutical industries is gaining access to natural products, including medicinal plants. This bottleneck is heightened for endangered species prohibited for large sample collection, even if they show biological hits. While cultivating the pharmaceutically interesting plant species may be a solution, it is not always possible to grow the organism outside its natural habitat. Plants affected by abiotic stress present a potential alternative source for drug discovery. In order to overcome abiotic environmental stressors, plants may mount a defense response by producing a diversity of PSMs to avoid cells and tissue damage. Plants either synthesize new chemicals or increase the concentration (in most instances) of existing chemicals, including the prominent bioactive lead compounds morphine, camptothecin, catharanthine, epicatechin-3-gallate (EGCG), quercetin, resveratrol, and kaempferol. Most PSMs produced under various abiotic stress conditions are plant defense chemicals and are functionally anti-inflammatory and antioxidative.

The major PSM groups are terpenoids, followed by alkaloids and phenolic compounds. We have searched the literature on plants affected by abiotic stress (primarily studied in the simulated growth conditions) and their PSMs (including pharmacological activities) from PubMed, Scopus, MEDLINE Ovid, Google Scholar, Databases, and journal websites. We used search keywords: “stress-affected plants,” “plant secondary metabolites, “abiotic stress,” “climatic influence,” “pharmacological activities,” “bioactive compounds,” “drug discovery,” and “medicinal plants” and retrieved published literature between 1973 to 2021. This review provides an overview of variation in bioactive phytochemical production in plants under various abiotic stress and their potential in the biodiscovery of therapeutic drugs. We excluded studies on the effects of biotic stress on PSMs.

초록

식물 이차 대사산물(PSM)은 

인체 건강에 필수적이며 많은 의약품의 골격을 구성합니다. 

실제로 

현존하는 약물의 25% 이상이 

PSM에 속합니다. 

신약 개발 및 제약 업계의 지속적인 과제 중 하나는 

약용 식물을 포함한 천연물에 대한 접근성을 확보하는 것입니다. 

생물학적 효능이 있더라도 

대량 샘플 채취가 금지된 멸종 위기종의 경우 

이러한 병목 현상은 더욱 심화됩니다. 

약학적으로 흥미로운 식물 종을 재배하는 것이 해결책이 될 수 있지만, 

자연 서식지 밖에서 유기체를 재배하는 것이 항상 가능한 것은 아닙니다. 

비생물학적 스트레스의 영향을 받는 식물은 

신약 개발을 위한 잠재적인 대안이 될 수 있습니다. 

비생물적 환경 스트레스 요인을 극복하기 위해 식물은

 세포와 조직 손상을 피하기 위해 다양한 

PSM을 생성하여 방어 반응을 일으킬 수 있습니다. 

식물은 

새로운 화학 물질을 합성하거나 

대부분의 경우 대표적인 생리 활성 납 화합물인 

모르핀, 캄포테신, 카타란틴, 에피카테킨-3-갈레이트(EGCG), 퀘르세틴, 레스베라트롤, 캠페롤을 포함한 

기존 화학 물질의 농도를 높입니다(대부분의 경우). 

morphine, camptothecin, catharanthine, epicatechin-3-gallate (EGCG), quercetin, resveratrol, and kaempferol.

다양한 비생물학적 스트레스 조건에서 생성되는 대부분의 PSM은 

식물 방어 화학물질로, 

항염증 및 항산화 기능을 합니다. 

주요 PSM 그룹은 

테르페노이드이며, 

알칼로이드와 페놀 화합물이 그 뒤를 잇습니다. 

비생물학적 스트레스에 영향을 받는 식물(주로 시뮬레이션 생육 조건에서 연구됨)과 그 PSM(약리 활성 포함)에 대한 문헌을 PubMed, Scopus, MEDLINE Ovid, Google Scholar, 데이터베이스 및 저널 웹사이트에서 검색했습니다. 검색 키워드를 사용했습니다: “스트레스에 영향을 받는 식물”, ‘식물 이차 대사산물’, ‘비생물적 스트레스’, ‘기후 영향’, ‘약리 활성’, ‘생리 활성 화합물’, ‘약물 발견’, ‘약용 식물’을 검색어로 사용하여 1973년부터 2021년까지 발표된 문헌을 검색했습니다. 

이 리뷰는 

다양한 비생물적 스트레스를 받는 식물의 

생리활성 파이토케미컬 생산 변화와 

치료약물의 생물학적 발견에 대한 잠재력에 대한 개요를 제공합니다. 

생물학적 스트레스가 

PSM에 미치는 영향에 대한 연구는 제외했습니다.

Keywords: secondary metabolites, climate change, drug discovery, abiotic stress

1. Introduction

Plant secondary metabolites (PSMs) are small molecules with diverse chemical structures and biological activities. Unlike primary metabolites, which are the main drivers of essential life functions, including cell formation, PSMs are neither necessary for primary life functions nor possess high-energy bonds [1]. However, PSMs play essential secondary physiological and biochemical functions that ensure plant fitness and survival, particularly concerning their interactions with the environment and coping with biotic and abiotic stress [1]. These factors, especially abiotic stressors (nutrient deficiencies, seasons, salinity, wounding, drought, light, UV radiation, temperature, greenhouse gases, and climate changes), cause significant perturbations in chemotypes and levels of PSMs production. For example, plants produce more terpenoids when exposed to high temperatures [2], and UV-B (280–315 nm) radiation induces tree foliage to produce more phenolic acids and flavonoids as protective pigments [3,4]. Phenolics and flavonoids are well-known for their antioxidative and anti-inflammatory properties [5,6,7]. Similarly, the production of antioxidative compounds such as glutathione, g-aminobutyric acid (GABA), terpenoids, and volatile organic compounds (VOCs) increases under elevated O3 [8].

PSMs are vital for human health and form many pharmaceutical drugs’ backbone. Indeed, more than 25% of the existing drugs belong to PSMs [9]. The most popular PSMs-derived drugs are morphine (isolated from Papaver somniferum), digitoxin (isolated from Digitalis purpurea), taxol (isolated from Taxus baccata), artemisinin (isolated from Artemisia annua) and quinine (isolated from Cinchona officinalis), vinblastine and vincristine (isolated from Catharanthus roseus); and aspirin (first isolated as salicylic acid from Filipendula ulmaria). Since plants exposed to various abiotic stress conditions produce many PSMs in higher concentrations as their coping mechanism [10,11,12], it presents opportunities for natural product researchers and pharmaceutical companies to explore the biochemical responses of plants to climatic stress for developing many novel therapeutics. However, there is no comprehensive literature review examining the scope of plants affected by abiotic stresses for drug discovery.

Therefore, this scoping review examines recent advances related to PSMs in plants affected by abiotic stress/or abiotic growth factors, their roles as protective phytochemicals, and their potential for novel drug lead compounds. Although primary metabolites such as carbohydrates [13,14] and peptides [15,16] are also known to play roles in the plant’s defense response, our review focuses on selected classes of PSMs, including flavonoids, terpenoids, alkaloids, saponins, tannins, and cyanogenic glycosides. We have collected published information on plants affected by abiotic stresses (primarily studied in the simulated growth conditions) and their PSMs (including pharmacological activities) from PubMed, Scopus, MEDLINE Ovid, Google Scholar, Databases, and journal websites using the following keywords: “stress-affected plants,” “plant secondary metabolites,” “bioactive compounds,” “abiotic stress,” “climatic influence,” “pharmacological activities,” “drug discovery,” and “medicinal plants.” We have retrieved published literature between 1973 to 2021 (only related to PSMs produced under ex situ growth conditions), analysed the content, and presented the information in the form of figures and tables. The chemical structures were drawn by using ChewDraw Professional software, and each structure was cross-checked for their correctness using ChemSpider and HMDB databases. We excluded studies on the effects of biotic stress on PSMs.

1. 소개

식물 2차 대사산물(PSM)은

다양한 화학 구조와 생물학적 활성을 가진 저분자 물질입니다.

세포 형성을 포함한 필수 생명 기능의 주요 동인인

1차 대사산물과 달리,

PSM은 1차 생명 기능에 필요하지도 않고

높은 에너지 결합을 가지고 있지도 않습니다[1].

그러나

PSM은

특히 환경과의 상호작용과 생물학적 및 비생물학적 스트레스에 대처하는 등

식물의 적합성과 생존을 보장하는

필수적인 2차 생리적 및 생화학적 기능을 수행합니다[1].

이러한 요인, 특히

비생물적 스트레스 요인(영양 결핍, 계절, 염분, 상처, 가뭄, 빛, 자외선, 온도, 온실가스, 기후 변화)은

화학적 유형과 PSM 생산 수준에 상당한 교란을 일으킵니다.

예를 들어,

식물은

고온에 노출되면 더 많은 테르페노이드를 생성하고[2],

UV-B(280~315nm) 복사는 나무 잎이 보호 색소로서

더 많은 페놀산과 플라보노이드를 생성하도록 유도합니다[3,4].

페놀산과 플라보노이드는

항산화 및 항염증 특성으로 잘 알려져 있습니다 [5,6,7].

마찬가지로

글루타티온,

GABA(G-아미노낙산),

테르페노이드,

휘발성 유기 화합물(VOC)과 같은 항산화 화합물의 생성은

높은 O3에서 증가합니다[8].

PSM은

인체 건강에 필수적이며

많은 의약품의 근간을 형성합니다.

실제로

현존하는 약물의 25% 이상이

PSM에 속합니다[9].

가장 널리 사용되는

PSM 유래 약물은

모르핀(파파버 솜니페룸에서 분리),

디지톡신(디지털리스 퍼퓨레아에서 분리),

탁솔(탁수스 바카타에서 분리),

아르테미시닌(아르테미시아 아누아에서 분리) 및

퀴닌(신초나 오피시날리스에서 분리),

빈블라스틴과 빈크리스틴(카타란투스 로제우스에서 분리),

아스피린(필리펜둘라 울마리아에서 살리실산으로 처음 분리) 등이 있습니다.

다양한 비생물적 스트레스 조건에 노출된 식물은 대처 메커니즘으로 더 높은 농도의 많은 PSM을 생성하기 때문에[10,11,12], 천연물 연구자와 제약 회사는 기후 스트레스에 대한 식물의 생화학적 반응을 탐구하여 많은 새로운 치료제를 개발할 수 있는 기회를 제공합니다. 그러나 신약 개발을 위해 비생물학적 스트레스의 영향을 받는 식물의 범위를 검토한 종합적인 문헌 검토는 아직 없습니다.

따라서

이 범위 검토에서는

비생물적 스트레스/비생물적 성장 인자의 영향을 받는 식물의 PSM과 관련된

최근의 발전, 보호 피토케미컬로서의 역할, 새로운 약물 선도 화합물에 대한

잠재력을 검토합니다.

탄수화물[13,14] 및 펩타이드[15,16] 같은 주요 대사산물도

식물의 방어 반응에 중요한 역할을 하는 것으로 알려져 있지만,

본 리뷰에서는

플라보노이드,

테르페노이드,

알칼로이드,

사포닌, 탄닌 및 시아노제닉 배당체를 포함한

일부 PSM에 초점을 맞추고 있습니다.

비생물학적 스트레스에 영향을 받는 식물(주로 시뮬레이션 생육 조건에서 연구됨)과 그 PSM(약리 활성 포함)에 대한 공개된 정보를 다음 키워드를 사용하여 PubMed, Scopus, MEDLINE Ovid, Google Scholar, 데이터베이스 및 저널 웹사이트에서 수집했습니다: “스트레스에 영향을 받는 식물”, ‘식물 이차 대사산물’, ‘생리 활성 화합물’, ‘비생물 스트레스’, ‘기후 영향’, ‘약리 활성’, ‘약물 발견’, ‘약용 식물’. 1973년부터 2021년까지 발표된 문헌(현장 생장 조건에서 생산된 PSM과 관련된 것만)을 검색하여 내용을 분석하고 그림과 표의 형태로 정보를 제시했습니다. 화학 구조는 ChewDraw Professional 소프트웨어를 사용하여 그렸으며, 각 구조는 ChemSpider 및 HMDB 데이터베이스를 사용하여 정확성을 교차 확인했습니다. 생물학적 스트레스가 PSM에 미치는 영향에 대한 연구는 제외했습니다.

2. Plant Secondary Metabolites and Their Biological Roles

Generally, all plants produce secondary metabolites for defense, attraction, communication, and mediating stress [17]. For example, plants produce VOCs as defense molecules, and they are known to function as antimicrobial and insect repellent agents [18]. More than 200,000 PSMs have been identified [19], and with more than 391,000 plant species known worldwide [20], there is space for more discoveries. Some PSMs are specific to certain related plant taxa [21], and their concentrations can vary between populations and individual plants with plant ontogeny and tissue type [22,23]. These PSM variations can be due to genetic variability, but their concentrations are affected by environmental abiotic factors (growth conditions) such as those expected to intensify with climate change (e.g., heat stress, drought, UV radiation, and O3) [24], and herbivore and pathogen attacks [25,26]. Based on a biosynthetic pathway and chemical structure, PSMs have broadly been categorized into three major groups: (i) terpenoids (plant volatiles, sterols, carotenoids, saponins, and glycosides), (ii) phenolic compounds (flavonoids, phenolic acids, lignin, lignans, coumarins, stilbenes, and tannins), and (iii) nitrogen-containing compounds (alkaloids, glucosinolates, and cyanogenic glycosides) [27,28,29,30].

2. 식물의 이차 대사산물과 생물학적 역할

일반적으로 모든 식물은

방어, 유인, 의사소통, 스트레스 매개 등을 위해

이차 대사산물을 생산합니다 [17].

예를 들어,

식물은 방어 분자로서 VOC를 생성하며,

이는 항균 및 방충제 역할을 하는 것으로 알려져 있습니다 [18].

200,000개 이상의 PSM이 확인되었으며[19],

전 세계적으로 391,000종 이상의 식물이 알려져 있으므로[20],

더 많이 발견될 수 있는 여지가 있습니다.

일부 PSM은 특정 관련 식물 분류군에 국한되어 있으며[21], 그 농도는 식물 발생과 조직 유형에 따라 집단과 개별 식물에 따라 다를 수 있습니다[22,23]. 이러한 PSM의 변화는 유전적 다양성 때문일 수 있지만, 그 농도는 기후 변화(예: 열 스트레스, 가뭄, 자외선, O3)[24], 초식동물 및 병원균 공격[25,26] 등의 환경 비생물적 요인(성장 조건)에 의해 영향을 받습니다.

생합성 경로와 화학 구조에 따라 PSM은

크게 세 가지 주요 그룹으로 분류됩니다:

(i) 테르페노이드(식물 휘발성 물질, 스테롤, 카로티노이드, 사포닌 및 배당체),

(ii) 페놀 화합물(플라보노이드, 페놀산, 리그닌, 리그난, 쿠마린, 스틸벤 및 탄닌),

(iii) 질소 함유 화합물(알칼로이드, 글루코시놀레이트 및 시아노제닉 배당체) [27,28,29,30]이

그것입니다.

2.1. Terpenoids

Terpenoids or isoprenoids are one of the most structurally diverse naturally occurring PSMs, with the main skeleton consisting of five-carbon isopentyl units, called 2-methyl-1,3-butadiene, or isoprene. Terpenes contain only isoprene units, while terpenoids have additional functional groups, such as ketone or heterocyclic and hydroxyl rings. Based on structural construction, terpenoids can be considered as two types, aliphatic (e.g., geraniol) and cyclic (e.g., limonene) terpenoids. Since terpenoids contain many isoprene units, they are divided into various groups, as described below (Figure 1):

•  
•  
•  
•  
•  
•  
•  

Figure 1.

Representative examples of terpenoid plant secondary metabolites.

Terpenoids are formed from the meval‎onate pathway inside cytosol or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway inside the plastid [31]. The biosynthetic precursors of terpenoids include geranyl diphosphate (GPP) for monoterpenes; farnesyl diphosphate (FPP) for sesquiterpenes; and geranylgeranyl diphosphate (GGPP) for diterpenes [32]. An in-depth discussion on terpenoids’ biosynthetic pathway and structural diversity is covered by Aharoni et al. (2005) and Song et al. (2014) in their review [31,32]. More than 30,000 terpenes have been reported to date [33]. They are mostly phytohormones (e.g., gibberellins), photosynthetic pigments (e.g., phytol, carotenoids such as α-carotene and β-carotene), and carriers (e.g., ubiquinone, plastoquinone) in the electron chain transport systems [34,35]. The role of terpenoids is to protect plants directly (e.g., releasing phytoalexins after pathogen attacks) or indirectly by producing mixtures of volatile organic compounds (VOCs) to attract carnivores of their herbivores [36]. Phytoalexins are antimicrobial compounds produced after microbes’ challenge plants, and it is reviewed in-depth by González-Lamothe et al. [37]. VOCs include terpenoids (isoprene or hemiterpenoids and monoterpenoids), alkanes, alkenes, carbonyls, alcohols, esters, ethers, and acids [18]. VOCs are involved in plant-plant or plant-insect interactions, but some terpenoids act as lipid-soluble antioxidants inducing resistance to stress [38].

Several terpenoids have shown defensive roles against biotic and abiotic stresses in plants. Dahham et al. (2015) [39] and Porres-Martínez et al. (2016) [40] reported antioxidant activities of terpenes (sesquiterpene b-caryophyllene, and monoterpenes 1,8-cineole and α-pinene, respectively), suggesting their function in overcoming abiotic-induced oxidative stress. Terpenoids are also reported to protect plants from photodamage and oxidative stress by supporting photorespiration [41]. Carotenoids are the best-known terpenoids involved in photoprotection [42]. Other examples of defensive terpenes in plants are triterpene glycosides (or saponins) such as α-tomatine in the fruits and leaves of tomatoes [43] and avenacin in oat (Avena sativa) roots [44]. Avenacin and α-tomatine are important pre-formed antimicrobial compounds, commonly referred to as phytoanticipins, and they have defensive roles against microbial attacks [37]. Saponins are another group of compounds under terpenoids with triterpenes or steroidal aglycones linked to one or more sugar chains [45], but some saponins such as steroidal glycoalkaloids have a nitrogen atom in their aglycone chemical structure [45,46]. Similarl to many other PSMs, the amount and distribution of saponins in plants are influenced by season, biotic and abiotic stresses, and plant developmental stage. For example, maximum saponin production in Phytolacca dodecandra L’Hér. [47] and Dioscorea pseudojaponica Yamamoto [48] occurs during fruit and tuber development to prevent fruit loss and enable seed maturation. Under stress conditions, saponin levels in plants increase through jasmonate and salicylate signaling pathways [45].

테르페노이드 식물 이차 대사 산물의 대표적인 예입니다.

테르페노이드는

세포질 내부의 메발로네이트 경로 또는

플라스티드 내부의 2-C-메틸-D-에리스리톨-4-포스페이트(MEP) 경로에서 형성됩니다[31].

테르페노이드의 생합성 전구체에는

모노테르펜의 경우 제라닐 디포스페이트(GPP),

세스퀴테르펜의 경우 파네실 디포스페이트(FPP),

디테르펜의 경우 제라닐게라닐 디포스페이트(GGPP)가 포함됩니다 [32].

테르페노이드의 생합성 경로와 구조적 다양성에 대한 심도 있는 논의는 Aharoni 등(2005)과 Song 등(2014)의 리뷰에서 다루고 있습니다 [31,32].

현재까지

30,000개 이상의 테르펜이 보고되었습니다 [33].

이들은 대부분

식물 호르몬(예: 지베렐린),

광합성 색소(예: 피톨, α-카로틴 및 β-카로틴과 같은 카로티노이드) 및

전자 사슬 수송 시스템의 운반체(예: 유비퀴논, 플라스토퀴논)입니다 [34,35].

테르페노이드의 역할은

직접적으로(예: 병원균 공격 후 피토알렉신 방출) 식물을 보호하거나

휘발성 유기 화합물(VOC)의 혼합물을 생성하여

간접적으로 초식동물의 육식동물을 유인하는 것입니다[36].

피토알렉신은

미생물이 식물에 도전한 후 생성되는 항균 화합물로,

곤살레스-라모테 등[37]이 심도 있게 검토한 바 있습니다.

VOC에는

테르페노이드(이소프렌 또는 헤미테르페노이드 및 모노테르페노이드),

알칸, 알켄, 카르보닐, 알코올, 에스테르, 에테르 및 산이 포함됩니다[18].

VOC는

식물-식물 또는 식물-곤충 상호 작용에 관여하지만

일부 테르페노이드는 지용성 항산화제로서

스트레스에 대한 저항성을 유도하는 역할을 합니다[38].

몇몇 테르페노이드는

식물의 생물학적 및 비생물학적 스트레스에 대해

방어적인 역할을 하는 것으로 나타났습니다.

Dahham 등(2015) [39]과 Porres-Martínez 등(2016) [40]은

테르펜(세스키테르펜 b-카리오필렌, 모노테르펜 1,8-시네올 및 α-피넨)의 항산화 활성을 보고하여

비생물성 유발 산화 스트레스 극복 기능을 시사했습니다.

테르페노이드는 또한 광흡수를 지원하여

광손상 및 산화 스트레스로부터 식물을 보호하는 것으로 보고되었습니다 [41].

카로티노이드는

광 보호에 관여하는

가장 잘 알려진 테르페노이드입니다 [42].

식물의 방어 테르펜의 다른 예로는

토마토의 열매와 잎에 있는 α-토마틴[43]과

귀리(아베나 사티바) 뿌리에 있는 아베나신[44]과 같은 트리테르펜 배당체(또는 사포닌)가 있습니다.

아베나신과 α-토마틴은

일반적으로 피토안티핀이라고 불리는 중요한 사전 형성된 항균 화합물로,

미생물 공격에 대한 방어 역할을 합니다[37].

사포닌은

하나 이상의 당쇄에 연결된 트리테르펜 또는

스테로이드계 아글리콘을 가진 테르페노이드 아래의 또 다른 화합물 그룹이지만 [45],

스테로이드계 글리코알칼로이드와 같은 일부 사포닌은

아글리콘 화학 구조에 질소 원자가 있습니다 [45,46].

다른 많은 PSM과 마찬가지로

식물의 사포닌 양과 분포는

계절, 생물학적 및 비생물학적 스트레스, 식물 발달 단계에 영향을 받습니다.

예를 들어,

최대 사포닌 생산량은

피토라카 도데칸드라 레르. [47] 및 Dioscorea pseudojaponica Yamamoto [48] 과일과 괴경 발달 중에 발생하여

과일 손실을 방지하고 종자 성숙을 가능하게 합니다.

스트레스 조건에서

식물의 사포닌 수치는

자스모네이트 및 살리실레이트 신호 경로를 통해

증가합니다 [45].

2.2. Phenolic Compounds

More than 8000 phenolic compounds are reported from plants, of which half of them are flavonoids (approximately 4000–4500 compounds) such as aglycone, glycosides, and methylated derivatives [6,49]. Phenolics exhibit diverse structures from single aromatic rings (e.g., in phloroglucinol, gentisic acid, ferulic acid, caffeic acid, and vanillin) to complex polymeric structures such as in lignins (e.g., coniferyl alcohol), coumarins (e.g., scopoletin), phenolic quinones (e.g., juglone), tannins (e.g., ellagic acid), and flavonoids [50,51]. Among phenolic group compounds, flavonoids are the most abundant, and stilbenes and lignans are less common.

Flavonoids are a diverse secondary metabolite group with a wide array of functions, including protection against stress. Flavonoids comprise seven sub-groups (Figure 2) (flavones, flavonols, flavanones, isoflavonoids, flavan-3-ols or catechins, and anthocyanins) [52,53] based on the C-ring carbon to which B-ring is attached, and also based on the degree of oxidation and unsaturation of their C-ring [53]. Flavones contain a double bond between positions 2 and 3 and a ketone functional group in position 4 of the C-ring. In comparison, flavonols have a hydroxy group at position 3 of the C-ring and are sometimes glycosylated. Unlike flavones, flavonones are saturated with a double bond between positions 2 and 3 of the C-ring. Flavan-3-ols have a hydroxyl group in position 3 of the C-ring, but there is no double bond between positions 2 and 3 [53]. Although the metabolic role of phenolics is not well-defined, their protective functions in plants are attributed to their ability to scavenge free radicals and filter harmful UV radiations [54,55].

Ferulic acid, caffeic acid, and p-coumaric acid (hydroxycinnamic acid derivatives) are some of the best-known UV-B attenuators in plants [56]. Flavonoids help plants adjust to extreme heat and cold [57] through increasing accumulation. When Schulz et al. (2016) [58] analyzed the expression‎ of flavonoids in 20 mutants of two different Arabidopsis thaliana accessions (Col-0 and Ler) in response to freezing and cold acclimation (14 days at 4 °C), 19 mutants, which are gene-knock outs, did not exhibit flavonoid biosynthesis, with an exception to pap1-D mutant. A similar observation of increasing concentrations in flavonoids (anthocyanins and flavonols) was also reported by Pastore et al. (2017) [59] in grapevine berries, but tannins did not show any changes. The role of flavonoids in UV protection is also supported by Bieza and Lois’ work [60], in which they have isolated an Arabidopsis mutant tolerant to high levels of UV-B radiations. Such protective flavonoids are reported more in plants thriving in colder climates at higher elevations and semi-arid environments [61]. Flavonoid-based plant pigments, such as anthocyanins synthesized in the last step of the flavonoid biosynthesis pathway under UV stress upon acylation, can absorb UV radiation and scavenge ROS [62,63]. If not kept under control, ROS can cause direct damage to plants through the oxidation of essential biomolecules, leading to the accumulation of more ROS and ultimately programmed cell death [64].

2.2. 페놀 화합물

식물에서 8000개 이상의 페놀 화합물이 보고되었으며,

이 중 절반은

아글리콘, 배당체 및 메틸화 유도체와 같은

플라보노이드(약 4000-4500개 화합물)입니다 [6,49].

페놀류는

단일 방향족 고리(예: 플로로글루시놀, 젠티산, 페룰산, 카페산, 바닐린)에서부터

리그닌과 같은 복잡한 고분자 구조(예 코니페릴 알코올),

쿠마린(예: 스코폴레틴),

페놀 퀴논(예: 주글론),

탄닌(예: 엘라그산) 및 플라보노이드 [50,51].

페놀기 화합물 중 플라보노이드가

가장 풍부하고

스틸벤과 리그난은 덜 일반적입니다.

플라보노이드는

스트레스에 대한 보호 등 다양한 기능을 가진

다양한 이차 대사 산물 그룹입니다.

플라보노이드는

B-링이 부착된 C-링 탄소와 C-링의 산화 및 불포화 정도에 따라

7개의 하위 그룹(플라본, 플라보놀, 플라바논, 이소플라보노이드, 플라반-3-올 또는 카테킨, 안토시아닌)[52,53]으로

구성됩니다[그림 2]으로 분류됩니다.

플라본은 2번과 3번 위치 사이에 이중 결합이 있고,

4번 위치에는 케톤 작용기가 있습니다.

이에 비해 플라보놀은 C- 고리의 3번째 위치에 하이드 록시 그룹이 있으며

때때로 글리코 실화됩니다.

플라본과 달리 플라보논은 C- 고리의 2번과 3번 위치 사이에 이중 결합으로 포화되어 있습니다. 플라반-3-올은 C- 고리 3번 위치에 수산기를 가지고 있지만, 2번과 3번 위치 사이에는 이중 결합이 없습니다[53].

페놀류의 대사적 역할은 잘 정의되어 있지 않지만

식물에서의 보호 기능은 자유 라디칼을 제거하고

유해한 자외선을 필터링하는 능력에 기인합니다 [54,55].

페룰산, 카페산, p-쿠마린산(하이드록시신남산 유도체)은

식물에서 가장 잘 알려진 UV-B 감쇠제 중 일부입니다[56].

플라보노이드는

축적을 증가시켜 식물이 극심한 더위와 추위에 적응하도록 돕습니다[57].

Schulz 등(2016)[58] 두 가지 다른 애기장대(Arabidopsis thaliana)의 20개 돌연변이체(Col-0 및 Ler)에서 동결 및 저온 적응(4°C에서 14일)에 대한 플라보노이드 발현을 분석했을 때, 유전자 녹아웃인 19개 돌연변이체는 pap1-D 돌연변이를 제외하고는 플라보노이드 생합성을 나타내지 않았다고 합니다. 포도나무 열매에서 플라보노이드(안토시아닌과 플라보놀)의 농도가 증가하는 유사한 관찰이 Pastore 등(2017)[59]에 의해 보고되었지만 탄닌은 변화가 나타나지 않았습니다. 자외선 차단에서 플라보노이드의 역할은 높은 수준의 UV-B 방사선에 내성이 있는 애기장대 돌연변이를 분리한 Bieza와 Lois의 연구[60]에서도 뒷받침됩니다. 이러한 보호 플라보노이드는 고지대의 추운 기후와 반건조 환경에서 번성하는 식물에서 더 많이 보고되고 있습니다 [61]. 아실화 시 자외선 스트레스 하에서 플라보노이드 생합성 경로의 마지막 단계에서 합성되는 안토시아닌과 같은 플라보노이드 기반 식물 색소는 자외선을 흡수하고 ROS를 청소할 수 있습니다 [62,63].

ROS를 제어하지 않으면

필수 생체 분자의 산화를 통해 식물에 직접적인 손상을 일으켜

더 많은 ROS를 축적하고 궁극적으로 세포 사멸을 유도할 수 있습니다 [64].

Figure 2.

Open in a new tab

Representative examples of different subgroups of flavonoids: a major phenolic group of secondary metabolites.

Flavonoids such as quercetin can chelate transition metals (for example, Fe), consequently inhibiting Fenton reaction (conversion of H2O2 to toxic OH• radical), thereby creating a robust antioxidative environment in the plants [65]. Phenolics are also known to play a strategic role in reproduction as frugivore attractants that promote seed dispersal (e.g., anthocyanidins and anthocyanins such as cyanidin-3-glucoside) [66,67].

2.3. Nitrogen-Containing Compounds

2.3.1. Alkaloids

Alkaloids are the major group of plant defense molecules that contain a nitrogen atom(s) derived from the decarboxylation of amino acids and are known to occur in 20% of plant species [32]. There are seven types of alkaloids based on their amino acid precursors (Figure 3). Tropane, pyrrolidine, and pyrrolizidine alkaloids are derived from ornithine amino acid precursors; benzylisoquinoline from tyrosine amino acid precursors; indolequinoline from tryptophane amino acid precursors; and quinolizidine and piperidine alkaloids from lysine amino acid precursors [68]. Alkaloids are widely distributed among plant lineages and are particularly abundant in angiosperms. Individual plant species may contain fewer than five to more than 30 alkaloids (e.g., 74 alkaloids in Catharanthus roseus, 54 in Strychnos toxifera, and 39 in Rauwolfia serpentina) [68,69]. Generally, a plant family produces only one type of alkaloid, although a few families such as Solanaceae and Rutaceae accumulate a broad spectrum of alkaloids [70]. For example, Duboisia myoporoides R.Br. contains both a tropane alkaloid (hyoscine) and a pyridine alkaloid (nicotine) [71].

More than 20,000 alkaloids have been isolated, of which about 600 are known to be bioactive [72], but the exact physiological or metabolic role of alkaloids in plants remains poorly understood [68]. Alkaloids are best known for their defensive role as insect-herbivore deterrents owing to their characteristic bitter taste [73]. Thus, according to Levin [69], most alkaloid-bearing plants are found in the tropics, where intensive herbivore pressure is present. Defensive or toxic alkaloids in plants may be produced either by the plants themselves or by their symbiotic partners [74,75]. For example, the symbiotic endophyte Epichloe coenophiala in tall fescue grass [Lolium arundinaceum (Schreb.) Darbysh, syn. Festuca arundinacea (Schreb.), and Schedonorus arundinaceus (Schreb.) Dumort.) produces insecticidal alkaloids, lolines, and ergot, which cause ‘fescue toxicosis’ in grazing animals [76]. Alkaloid biosynthesis in plants is genetically controlled, but environmental factors such as light (UV), temperature, moisture, and soil nutrients also influence the type and rate of alkaloid production [76,77].

2.3. 질소 함유 화합물

2.3.1. 알칼로이드

알칼로이드는

아미노산의 탈카르복실화에서 파생된 질소 원자를 포함하는 식물 방어 분자의 주요 그룹으로,

식물 종의 20%에서 발생하는 것으로 알려져 있습니다[32].

알칼로이드는

아미노산 전구체를 기준으로

7가지 유형이 있습니다(그림 3).

트로판, 피롤리딘, 피롤리지딘 알칼로이드는

오르니틴 아미노산 전구체에서,

벤질리소퀴놀린은 티로신 아미노산 전구체에서,

인돌퀴놀린은 트립토판 아미노산 전구체에서,

퀴놀리지딘과 피페리딘 알칼로이드는 라이신 아미노산 전구체에서 유래합니다 [68].

알칼로이드는

식물 계통에 널리 분포하며

특히 속씨 식물에 풍부합니다.

개별 식물 종은

5개 미만에서 30개 이상의 알칼로이드를 함유할 수 있습니다

(예: 카타란투스 로제우스의 알칼로이드 74개, 스트라이크노스 톡시페라 54개, 라우울피아 세펜티나 39개) [68,69].

일반적으로 한 식물군은

한 가지 유형의 알칼로이드만 생산하지만,

솔라나세아와 루타세아와 같은 몇몇 식물군은

광범위한 스펙트럼의 알칼로이드를 축적합니다 [70].

예를 들어,

두보이시아 미오포로이데스 R.Br.에는

트로판 알칼로이드(효신)와 피리딘 알칼로이드(니코틴)가 모두 포함되어 있습니다[71].

20,000개 이상의 알칼로이드가 분리되었으며,

이 중 약 600개가 생리활성이 있는 것으로 알려져 있지만 [72],

식물에서 알칼로이드의 정확한 생리적 또는 대사적 역할은 아직 잘 알려져 있지 않습니다 [68].

알칼로이드는

특유의 쓴 맛으로 인해

곤충-초식동물 억제제로서의 방어적 역할로 가장 잘 알려져 있습니다 [73].

따라서 Levin에 따르면 [69],

대부분의 알칼로이드 함유 식물은

초식동물의 집중적인 압력이 있는 열대 지방에서 발견됩니다.

식물의 방어 또는 독성 알칼로이드는

식물 자체 또는 공생 파트너에 의해 생성 될 수 있습니다 [74,75].

예를 들어, 키가 큰 페스큐 풀의 공생 내생균인 에피클로에 코에노피알라[Lolium arundinaceum (Schreb.) Darbysh, syn. Festuca arundinacea (Schreb.) 및 Schedonorus arundinaceus (Schreb.) Dumort.)는 살충 알칼로이드, 롤린 및 에르고트를 생성하여 방목 동물에게 '페스큐 중독증[76]'을 일으킵니다[76]. 식물의 알칼로이드 생합성은 유 전적으로 제어되지만 빛 (UV), 온도, 수분 및 토양 영양소와 같은 환경 요인도 알칼로이드 생산의 유형과 속도에 영향을 미칩니다 [76,77].

Figure 3.

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Representative examples of seven different types of alkaloids produced in plants and their chemical structure.

2.3.2. Cyanogenic Glycosides and Glucosinolates

Other N-containing defense compound groups include cyanogenic glycosides and glucosinolates. These two groups are also derived from amino acid precursors and are significantly less diverse in their structure, with over a hundred compounds known from each group. Cyanogenic glycosides are reported in more than 2500 plant species [78], including ferns, gymnosperms, and angiosperms, while glucosinolates have been reported only in the order Capparales and in the genus Drypetes of the Euphorbiaceae [79]. According to Vetter [78] and Gleadow and Moller [80], some of the widely distributed cyanogenic glycosides in the plant kingdom are linamarin and lotaustralin (in Compositae, Linaceae, Fabaceae, Papaveraceae, and Euphorbiaceae); prunasin (in Myrtaceae, Polypodiaceae, Rosaceae, Saxifragaceae, Scrophulariaceae, and Myoporaceae); and dhurrin (in Poaceae and Euphorbiaceae) (Figure 4). Important food crops such as apple (Malus domestica), apricot (Prunus armeniaca), bamboo (Bambusa vulgaris), cassava (Manihot esculenta), cocoyam (Colocasia esculenta and Xanthosoma sagittifolium), and sorghum (Sorghum bicolor) are known to contain cyanogenic glycosides [81,82]. Cyanogenic glycosides and glucosinolates are generally higher in young leaves [83,84] and reproductive tissues [23,83,84,85]. They are toxic in higher concentrations [86], but in response to the low light, some plants such as tropical Prunus turneriana tend to accumulate more cyanogenic glycosides in older leaves. Although cyanogenic glycosides and glucosinolates in plants also respond to climatic stress such as drought and increased temperatures [80,86], they are not discussed in the following sections of this review.

2.3.2. 시아노제닉 배당체 및 글루코시놀레이트

다른 N-함유 방어 화합물 그룹에는 시아노제닉 배당체와 글루코시놀레이트가 있습니다. 이 두 그룹도 아미노산 전구체에서 파생되며 구조가 훨씬 덜 다양하며 각 그룹에서 알려진 화합물은 100개 이상입니다.

시아노제닉 배당체는

양치류, 겉씨식물, 속씨식물을 포함하여

2500종 이상의 식물 종에서 보고된 반면[78],

글루코시놀레이트는 카파랄레스와 마른잎식물과의 드라이페테스 속[79]에서만 보고된 바 있습니다.

베터[78]와 글로우와 몰러[80]에 따르면

식물계에 널리 분포하는 시아노제닉 배당체 중 일부는

리마린과 로타우스트랄린(Compositae, Linaceae, Fabaceae, Papaveraceae 및 Euphorbiaceae에 속함)입니다;

프루나신(미나리아재비과, 국화과, 장미과, 삭시프라과, 스크롭풀과, 미나리아재비과); 그리고

두린(두릅과, 유포르비과)(그림 4).

사과(말루스 도메스티카),

살구(프루누스 아르메니아카),

대나무(밤부사 벌가리스),

카사바(마니핫 에스큘렌타),

코코얌(콜로시아 에스큘렌타 및 잔토소마 사지티폴리움),

수수(소르그넘 바이컬러) 등 중요한 식량 작물에는 시아노제닉 글리코사이드가 들어 있는 것으로 알려져 있습니다[81,82].

시안배당체와 글루코시놀레이트는

일반적으로 어린 잎 [83,84] 및 생식 조직에서 더 높습니다 [23,83,84,85].

이들은 더 높은 농도에서 독성이 있지만 [86],

낮은 빛에 반응하여 열대 푸르누스 터너리아나와 같은 일부 식물은

오래된 잎에 더 많은 시아노겐성 배당체를 축적하는 경향이 있습니다.

식물의 시아노겐성 배당체와 글루코시놀레이트도 가뭄 및 온도 상승과 같은 기후 스트레스에 반응하지만[80,86], 이 리뷰의 다음 섹션에서는 이에 대해 설명하지 않습니다.

Figure 4.

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Examples of widely distributed cyanogenic glycosides in plant kingdom.

3. Factors Influencing PSMs Production in Plants

Vickers et al. [87] have proposed two hypothetical mechanisms by which plants may respond to multiple external stressors: membrane stabilization and direct antioxidative scavenging of reactive oxygen species (ROS) generated under stressful conditions and to attract pollinators [88]. Under oxidative stress, plants either directly catalyze ROS to less harmful compounds using enzymes such as superoxide dismutase, catalase, and peroxidase or mediate enzymatic regeneration of antioxidants (e.g., monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase) [64]. Non-volatile isoprenoids such as tocopherols, zeaxanthin, and carnosic acid can scavenge ROS directly by reactions through hydroxyl radicals [89,90]. Interestingly, rising global temperatures and other environmental variables such as atmospheric O3 concentration and UV-B radiation are known to increase plant stress and, therefore, enhance or limit PSMs production as means to cope with such stressors. VOC emissions from plants are triggered by wounding and tri-trophic interactions (plant-herbivorous-carnivorous arthropods) [91] and they are influenced by various environmental factors, including temperature, light, moisture, and pollutants [92]. Individual stress has a selective influence on PSMs production, either by inducing or inhibiting the compound biosynthesis or emission based on stress conditions in plants (Figure 5). While PSMs have diverse functions in plants, their production also depends on multiple factors [34,93]. The effects of abiotic stress on PSMs production are given in Table 1.

3. 식물의 PSM 생성에 영향을 미치는 요인들

비커스 등[87]은 식물이 여러 외부 스트레스 요인에 반응할 수 있는 두 가지 가상의 메커니즘을 제안했습니다:

막 안정화와 스트레스 조건에서 생성된 활성 산소 종(ROS)의 직접 항산화 제거 및 수분 매개자 유인 [88].

산화 스트레스 하에서 식물은 슈퍼옥사이드 디스뮤타제, 카탈라아제, 퍼옥시다제와 같은 효소를 사용하여

ROS를 덜 해로운 화합물로 직접 촉매하거나

항산화 물질(예: 모노하이드로아스코르베이트 환원효소, 탈하이드로아스코르베이트 환원효소 및 글루타티온 환원효소)의 효소 재생을 매개합니다[64].

토코페롤, 제아잔틴, 카르노산과 같은

비휘발성 이소프레노이드는

하이드 록실 라디칼을 통한 반응으로

ROS를 직접 청소할 수 있습니다 [89,90].

흥미롭게도

지구 기온의 상승과 대기 중 오존 농도 및 UV-B 복사와 같은 기타 환경 변수는

식물의 스트레스를 증가시키고,

따라서 이러한 스트레스 요인에 대처하기 위한 수단으로

PSM 생성을 강화하거나 제한하는 것으로 알려져 있습니다.

식물의 VOC 배출은 상처와 삼영양 상호작용(식물-초식-육식 절지동물)에 의해 촉발되며[91], 온도, 빛, 수분, 오염 물질 등 다양한 환경 요인의 영향을 받습니다[92]. 개별 스트레스는 식물의 스트레스 조건에 따라 화합물 생합성 또는 방출을 유도하거나 억제하여 PSM 생성에 선택적으로 영향을 미칩니다(그림 5).

PSM은

식물에서 다양한 기능을 수행하지만,

그 생산 또한 여러 요인에 따라 달라집니다 [34,93].

비생물학적 스트레스가

PSM 생산에 미치는 영향은 표 1 에 나와 있습니다.

Figure 5.

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Abiotic stresses and their influence on the types of secondary metabolites in plants (adapted from [94,95,96,97]). Abbreviations: UV radiation = ultraviolet radiation; PSMs = plant secondary metabolites; O3 = ozone; CO2 = carbon dioxide; Isopr = isoprenoids; MT = monoterpenes; SQT = sesquiterpenes; phe. acids = phenolic acids.

Table 1.

Plant secondary metabolites produced in response to abiotic stresses and their reported pharmacological properties.

Stress Condition(s)Plant Species (Family)PSMs ProducedEffects on PSMs ConcentrationCompound ClassBioactive CompoundsReported Pharmacological Properties

Cold stress	Catharanthus roseus (Apocynaceae) [98]	vindoline	Decrease	Alkaloids	vindoline	Antidiabetic [99]
Cold stress	Glycine max (Fabaceae) [94]	genistein, daidzein	Increase	Phenolics	genistein, daidzein	Antiproliferative [95,96]
Cold stress	Solanum lycopersicon (Solanaceae) [87,97]	(Z)-3-hexenol and (E)-2-hexenal (dominant); 1-hexanol and 1,4-hexadienal (smaller quantities)	Increase	Fatty Acyls	(E)-2-hexenal	Antibacterial [100]
Cold stress		β-phellandrene, (E)-β-ocimene	Increase	Terpenoids	NA	NA
Cold stress		δ-elemene, α-humulene and β-caryophyllene (dominant); in severe cold: β-elemene is produced.	Increase	Terpenoids	δ-elemene, α-humulene and β-caryophyllene	Antiproliferative [101]; anticancer [102]; anti-inflammatory [103]
Cold stress	Zea mays (Poaceae) [104]	pelargonidin	Increase	Phenolics	pelargonidin	Antithrombotic [105]
Cold stress	Fagopyrum tartaricum (Polygonaceae) [106]	anthocyanins (e.g.,3-O-galactosides) and anthocyanidins (e.g., malvidin)	Increase	Phenolics	anthocyanins	Antioxidant [107]
Cold stress	Withania somnifera (Solanaceae) [108]	withanolide A, withaferin A	Increase	Terpenoids	withanolide A; withferin A	Neuroprotective [109]; anticancer [110]
Cold stress	Camellia sinensis (Theaceae) [111]	nerolidol glucoside	Increase	Terpenoids	NA	NA
Drought	Amaranthus tricolor (Amaranthaceae) [112]	hydroxybenzoic acids (gallic acid, vanillic acid, syringic acid, p-hydroxybenzoic acid, salicylic acid, ellagic acid), hydroxycinnamic acids (caffeic acid, chlorogenic acid, p-coumaric acid, ferulic acid, m-coumaric acid, sinapic acid, trans-cinnamic acid), flavonoids (iso-quercetin, hyperoside, rutin).	Increase	Phenolics (Flavonoids)	p-hydroxybenzoic acid	Antisickling activity [113]
Drought	Camellia sinensis (Theaceae) [114]	Epicatechins	Increase	Phenolics (Flavonoids)	epicatechins	Antioxidant [115]
Drought	Camptotheca acuminata (Nyssaceae) [116]	camptothecin	Increase	Alkaloids	camptothecin	Antitumour [117]
Drought (PEG-induced)	Catharanthus roseus (Apocyanaceae) [118]	vinblastine	Increase	Alkaloids	vinblastine	Anticancer [119]
Drought	Cistus clusii (Cistaceae) [120]	epigallocatechin gallate, epicatechin, epicatechin gallate, and ascorbic acid.	Increase	Phenolics (Flavonols)	epigallocatechin gallate	Anticancer [121]; antibacterial [122]
Drought	Crataegus laevigata, C. monogyna (Rosaceae) [123]	chlorogenic acid, catechin, (−)-epicatechin	Increase	Phenolics	chlorogenic acid, (−)-epicatechin	Antioxidant [124,125]
Drought	Glycine max (Fabaceae) [126]	trigonelline	Increase	Alkaloids	trigonelline	Antidiabetic [127]
Drought	Hypericum brasiliense (Hypericaceae) [128]	isouliginosin B, rutin, 1,5-dihydroxyxanthone	Increase	Phenolics	isouliginosin B, rutin,	Antinociceptive [129]; Anticancer [130]
		betulinic acid		Terpenoids	betulinic acid	Anticancer [131]
Drought	Lupinus angustifolius (Fabaceae) [132]	chinolizidin	Increase	Alkaloids	NA	NA
Drought	Papaver somniferum (Papaveraceae) [133]	morphine, codeine	Increase	Alkaloids	morphine, codeine	Analgesic [134,135]
Drought	Pinus sylvestris (Pinaceae) [136]	abietic acid	Increase	Terpenoids	abietic acid	Antiallergic [137]; anti-inflammatory [138]
Drought	Salvia miltiorrhiza (Lamiaceae) [139]	tanshinones, cryptotanshinone	Increase	Terpenoids	cryptotanshinone	Anticancer [140].
Drought	S. miltiorrhiza [139]	rosmarinic acid	Decrease	Phenolics	rosmarinic acid	Antioxidant [141]
		salvianolic acid	Increase		salvianolic acids	Antioxidant [142]
Drought	Scrophularia ningpoensis (Scrophulariaceae) [143]	catalpol, harpagide, aucubin, harpagoside	Increase	Glycosides	catalpol, aucubin	Hepatoprotective [144]; neuroprotective [145]
Ozone (O3) stress	S. lycopersicon [87,97]	α-carotene, β-carotene, violoxanthin	Increase	Terpenoids	β-carotene	Antioxidants [146]; anti-inflammatory [147]
		isoprene, α-pinene, β-pinene, myrcene, limonene, sabinene, (E)-β-ocimene, (Z)-β-ocimene, α-humulene, (E)-β-farnesene, (E,E)-α-farnesene, (E)-β-caryophyllene, δ-cadinene	Increase	Terpenoids	α-pinene; myrcene; limonene; α-humulene.	Anti-inflammatory [148]; anti-asthmatic [149]; antioxidant [150]; anti-inflammatory [151]
O3	Gingko biloba (Ginkgoaceae) [152]	ginkgolide A	Increase	Terpenoids	ginkgolide A	Neuroprotective [153]
Ultraviolet radiation-B (UV-B)	Arabidopsis thaliana (Brassicaceae) [154]	kaempferol 3-gentiobioside-7-rhamnoside; kaempferol 3,7-dirhamnoside.	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Brassica napus (Brassicaceae) [155]	quercetin 3-sophoroide-7-glucoside; quercetin 3-sinapyl sophoroside-7-glucoside	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Brassica oleracea (Brassicaceae) [156]	cyanidine glycosides; sinapyl alcohol	Increase	Phenolics (Flavoboids)	NA	NA
UV-B	C. roseus (Apocynaceae) [157,158]	catharanthine, vindoline	Increase	Alkaloids	catharanthine	Anticancer [159]
	Clarkia breweri (Onagraceae) [160]	eugenol, isoeugenol, methyleugenol, and isomethyleugenol	Increase	Phenolics	eugenol	Antifungal [161]; anti-inflammatory [162]
UV-B	Fagopyrum esculentum (Polygonaceae) [163]	rutin, quercetin, catechin	Increase	Phenolics	quercetin; catechin	Antioxidant [164]; anticancer and antioxidant [165,166]
UV-B	Gnaphalium luteoalbum (Asteraceae) [167]	calycopterin; 3’-methoxycalycopterin	Increase	Phenolics (Flavonoids)	calycopterin	Anticancer [168]
UV-B	G. viravira [169]	7-O-methyl araneol	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Hordeum vulgare (Poaceae) [170]	saponarin; luteolin	Increase	Phenolics (Flavonoids)	saponarin; luteolin	Antihypertensive [171]; antibacterial [172]
UV-B	Marchantia polymorpha (Marchantiaceae) [173]	luteolin 7-glucuronide; luteolin 3,4’-di-p-coumaryl-quercetin 3-glucoside.	Increase	Phenolics (Flavonoids)	NA	NA
UV-B	Quercus ilex (Fagaceae) [174]	acylated kaempferol glycosides	Increase	Phenolics (Flavonoids)	kaempferol	Anticancer [175]; anti-inflammatory [176]
Heat stress	C. acuminata [177]	10-hydroxycamptothecin	Increase	Alkaloids	10-hydroxycamptothecin	Anticancer [178]
Heat stress	Daucus carota (Apiaceae) [179,180,181]	α-terpinolene	Decrease	Terpenoids	α-terpinolene	Antioxidant and anticancer [182]
		α-caryophyllene, β-farnesene	Increase		NA	NA
		anthocyanins, coumaric and caffeic acid;	Increase	Phenolics	p-coumaric acid and caffeic acid	Antioxidant [183,184]
Heat stress	Q. rubra (Fagaceae) [185]	isoprene (2-methyl-1,3-butadiene)	Increase	Terpenoids	NA	NA
Heat stress	S. lycopersicon [87,97]	β-phellandrene (dominant), 2-carene, α-phellandrene, limonene; increased emission of (E)-β-ocimene after treatment above 46 °C; β-caryophyllene.	Increase	Terpenoids	α-phellandrene; β-caryophyllene	Antifungal [186]; anticancer and anti-inflammatory [102,103]
		α-humulene	Decrease		α-humulene	Anticancer [187]
Heat stress (increased humidity)	Centella asiatica (Apiaceae) [188]	asiaticoside	Increase	Phenolics	asiaticoside	Anti-cellulite agent [189]

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Abbreviations: NA: not available; LOX: lipoxygenase; UV: ultraviolet; ROS: reactive oxygen species.

3.1. Effects of Heat Stress on PSMs

Warming causes the accumulation of terpenoids, which usually have protective functions in mitigating environment-induced oxidative stress in plants [87,190]. For instance, tomato (S. lycopersicum) grown under heat stress (at 46 °C) emits higher levels of monoterpenes such as α-thujene, α-pinene, camphene, 2-carene, α-phellandrene, δ-3-carene (car-3-ene), α-terpinene, limonene, β-phellandrene, (E)-β-ocimene, and terpinolene; and also sesquiterpenes such as δ-elemene, β-elemene, α-humulene, and β-caryophyllene (Table 1) compared to controls [97]. In contrast, Nogués et al. [191] observed decreased emission of terpenes in Citrus monspeliensis grown under laboratory conditions at 35 °C; instead, increased assimilation of water-soluble antioxidant ascorbate indicates a shift from terpene-mediated to ascorbate-mediated ROS scavenging mechanism. Moreover, when C. monspeliensis was grown in the field, total terpene emission was higher during winter than in summer [191]. These contrasting findings suggest that terpene emissions under heat conditions could be species-specific and vary seasonally. Additionally, free fatty acids released by membrane phospholipase in response to heat (and cold) form lipoxygenase (LOX) products via lipoxygenase pathway, out of which C6 compounds (Z)-3-hexenal and (E)-2-hexenal are most common [97]. Wounded plants also release these two compounds within a few minutes [192,193]. Notably, (E)-2-hexenal acts as a chemical signal inducing the expression‎ of stress-related transcription factors such as HSFA2 (heat stress transcription factor A-2) and MBF1c (multiprotein-bridging factor 1c) [194]. Heat stress may cause the melting of cuticular lipids, thus increasing cuticular permeability [195], and extreme temperatures may rupture terpene-containing-glandular trichomes, releasing the contents into the air [97]. After exposure to cold and heat stresses, favorable pH conditions inside plastids favor increased terpene synthesis [97] (Figure 5).

3.1. 열 스트레스가 PSM에 미치는 영향

온난화는

일반적으로 식물에서 환경으로 인한 산화 스트레스를 완화하는 보호 기능을 가진

테르페노이드의 축적을 유발합니다 [87,190].

예를 들어,

토마토(S. 리코퍼시쿰)은 열 스트레스(46°C에서)를 받으면

α-투젠, α-피넨, 캄펜, 2-카렌, α-펠란드렌, δ-3-카렌(카-3-엔), α-테르피넨, 리모넨, β-펠란드렌, (E)-β-오시멘, 테르피놀렌 같은

높은 수준의 모노테르펜을 방출합니다;

그리고

δ-엘레멘, β-엘레멘, α-후뮬렌, β-카리오필렌과 같은

세스 퀴 테르펜 (표 1)도 대조군과 비교했습니다 [97].

이와 대조적으로, 노게스 등[191]은

35°C의 실험실 조건에서 자란 감귤류

몬스펠리엔시스에서 테르펜의 방출이 감소하는 것을 관찰했으며,

대신 수용성 항산화제 아스코르브산염의 동화 증가는

테르펜 매개에서 아스코르브산염 매개 ROS 소거 메커니즘으로의 전환을 나타냈다고 합니다.

또한, C. 몬스펠리엔시스를 밭에서 재배했을 때 총 테르펜 배출량은 여름보다 겨울에 더 높았습니다 [191]. 이러한 대조적인 결과는 더위 조건에서 테르펜 배출이 종에 따라 달라질 수 있으며 계절에 따라 달라질 수 있음을 시사합니다.

또한, 열(및 추위)에 반응하여 막 포스포리파제에 의해 방출된 유리 지방산은 리폭시게나제 경로를 통해 리폭시게나제(LOX) 생성물을 형성하며, 이 중 C6 화합물 (Z)-3-헥세날과 (E)-2-헥세날이 가장 흔합니다 [97]. 상처를 입은 식물도 몇 분 안에 이 두 화합물을 방출합니다 [192,193]. 특히 (E)-2-헥세날은 HSFA2(열 스트레스 전사인자 A-2) 및 MBF1c(다중 단백질 브리징 인자 1c)와 같은 스트레스 관련 전사인자의 발현을 유도하는 화학적 신호로 작용합니다[194].

열 스트레스는 큐

티클 지질의 용융을 유발하여 큐티클 투과성을 증가시킬 수 있으며 [195],

극한의 온도는 테르펜 함유 선상 트리코메를 파열시켜

내용물을 공기 중으로 방출할 수 있습니다 [97].

추위와 열 스트레스에 노출된 후,

플라스티드 내부의 유리한 pH 조건은

테르펜 합성을 증가시킵니다 [97] (그림 5).

Under simulated environmental conditions, heat stress damages membranes (e.g., thylakoid membrane) and disintegrates membrane protein complexes (e.g., photosystem II) [196], consequently decreasing the rate of photosynthesis. Plants counteract such damage through sustained synthesis and emission of terpenes [87,197]. Korankye et al. [197] proposed that plants produce more terpenes under stressful conditions by diverting carbon to a non-meval‎onate pathway, which otherwise could have been used in photosynthesis. Monoterpenes such as 1,8-cineole, α-terpinyl acetate, linalyl acetate, limonene, sabinene, myrcene, α-terpinen, β-ocimene, α-terpinolene, and γ-terpinene are most produced following decreased photosynthesis in plants [191,198]. Non-targeted PSMs profiling in tomatoes revealed higher concentrations of α-tocopherol and plastoquinone under 38 °C compared to lower temperatures (20 and 10 °C) [199]. Taken together with other studies [200,201], this suggests that these compounds function as electron carriers and facilitate photosynthesis in addition to their anti-oxidative functions. The photosynthetic rate also decreases under the increasing temperature as in Pueraria lobata [Willd.] Ohwi., and Quercus spp. when isoprene synthesis (non-meval‎onate pathway) was inhibited with fosmidomycin [202]. They suggest that isoprene improves thermotolerance in plants and helps photosynthetic apparatus recover after experiencing heat shock (i.e., temperature > 40 °C). Studies [203,204] suggest that plants tolerant to sunlight-induced heat flecks, O3, and ROS produce more isoprene than non-tolerant species. However, not all plants seem to produce isoprenoid compounds, but it varies among different plant species. For instance, when grown at 30 °C, Salix phylicifolia L. emitted isoprene, whereas Betula nana L. and Cassiope tetragona (L) D.Don emitted monoterpenes such as (Z)-2-hexenal, hexenyl butyrate, hexenyl acetate, and 3-hexenyl-methyl butanoate [205]. Heat stress also enhances the production of water-soluble antioxidants (e.g., ascorbate and glutathione) as well as lipid-soluble antioxidants (e.g., tocopherols) that scavenge increasing ROS [206,207]. For example, Lycopersicon esculentum Mill. Var. Amalia, after receiving heat shock at 45 °C for three hours, has been shown to produce more ascorbate and glutathione than its wild thermotolerant type Nagcarlang control under the same conditions [207]. Heat stress also affects flavonoids production as sweet basil (Ocimum basilicum L.) responds to high temperatures by producing flavonoids [208].

시뮬레이션된 환경 조건에서 열 스트레스는

막(예: 틸라코이드 막)을 손상시키고

막 단백질 복합체(예: 광합성 시스템 II)를 분해하여[196]

결과적으로 광합성 속도를 감소시킵니다.

식물은

테르펜의 지속적인 합성과 방출을 통해

이러한 손상에 대응합니다 [87,197].

코란케 등[197]은 식물이 스트레스가 많은 조건에서 광합성에 사용될 수 있는 탄소를 비메발레이트 경로로 전환하여 더 많은 테르펜을 생산한다고 제안했습니다. 1,8-시네올, α-테르피닐 아세테이트, 리날릴 아세테이트, 리모넨, 사비넨, 미르센, α-테르피넨, β-오시멘, α-테르피놀렌 및 γ-테르피넨과 같은 모노테르펜은 식물에서 광합성이 감소한 후 가장 많이 생성됩니다 [191,198]. 토마토의 비표적 PSM 프로파일링은 저온(20 및 10°C)에 비해 38°C에서 α-토코페롤과 플라스토퀴논의 농도가 더 높은 것으로 나타났습니다 [199]. 다른 연구 [200,201]와 함께 고려할 때, 이는 이러한 화합물이 전자 운반체로서 기능하고 항산화 기능 외에도 광합성을 촉진한다는 것을 시사합니다. 포스미도마이신으로 이소프렌 합성(비메발레이트 경로)을 억제했을 때, 온도가 상승할수록 광합성 속도가 감소하는 것은 푸에라리아 로바타[Willd.] 오위와 퀘르쿠스(Quercus spp.)에서도 마찬가지입니다 [202]. 이소프렌이 식물의 내열성을 개선하고 열충격(즉, 40°C 이상의 온도)을 경험한 후 광합성 장치가 회복하는 데 도움이 된다는 것을 시사합니다. 연구[203,204]에 따르면 햇빛에 의한 열반점, O3 및 ROS에 내성이 있는 식물은 내성이 없는 종보다 더 많은 이소프렌을 생성한다고 합니다. 그러나 모든 식물이 이소프레노이드 화합물을 생성하는 것은 아니며, 식물 종에 따라 차이가 있습니다. 예를 들어, 30°C에서 재배했을 때 살릭스 필리시폴리아 L.은 이소프렌을 방출하는 반면, 베툴라 나나 L.과 카시오페 테트라고나 (L) D.돈은 (Z)-2-헥세날, 헥세닐 부티레이트, 헥세닐 아세테이트 및 3-헥세닐-메틸 부타노에이트 같은 모노테르펜을 방출합니다 [205]. 열 스트레스는 또한 수용성 항산화제(예: 아스코르브산염 및 글루타티온)와 지용성 항산화제(예: 토코페롤)의 생성을 촉진하여 증가하는 ROS를 청소합니다[206,207]. 예를 들어, 리코퍼시콘 에스큘렌텀 밀. Var. 아말리아는 45°C에서 3시간 동안 열 충격을 받은 후 동일한 조건에서 야생 내열성 타입의 나그칼랑 대조군보다 더 많은 아스코르브산염과 글루타치온을 생성하는 것으로 나타났습니다 [207]. 스위트 바질(Ocimum basilicum L.)은 고온에 반응하여 플라보노이드를 생산하므로 열 스트레스는 플라보노이드 생산에도 영향을 미칩니다 [208].

3.2. Effects of Cold Stress on PSMs

Cold stress or low-temperature stress is either chilling (<20 °C) or freezing (<0 °C) temperature, and they adversely affect plants’ growth and development. Plants growing in sub-tropical and tropical areas are more sensitive to cold stress than temperate species [209]. Cold stress tolerance in plants is achieved through selective expression‎ of stress-defensive genes, which is reviewed by Chinnusamy et al. [210]. For instance, Jeon et al. [106] investigated transcripts and metabolites in six-day-old tartary buckwheat (Fagopyrum tartaricum) after cold exposure (at 4 °C, for various periods), observing upregulation of phenylpropanoid biosynthetic transcripts and significant accumulation of anthocyanins and proanthocyanidins, both antioxidative (Table 1) [107]. When two varieties of grapevine Vitis vinifera L. (cold tolerant – Maerchal Foch, and cold-sensitive – Kiszmisz Luczistyj) were exposed to 10/7 °C day/night cycle for 14 h photoperiod at 180–200 μm/(m2s) irradiance, the cold-tolerant variety had higher total phenolic compound content when assessed using the Folin-Ciocalteu’s reagent [211]. Subsequently, when they tested the antioxidant capacities of leaf extracts from two varieties by DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay, leaves from cold-tolerant varieties yielded better activity.

Another exciting example of the role of PSMs in plants under cold stress is the medicinal plant, Indian ginseng (Withania somnifera L.), which is the primary source of biologically active withanolides. Mir et al. [108] studied the accumulation of withanolides in response to cold stress in two genotypes of W. somnifera (AGB002―wild genotype and AGB025―cultivated genotype). After subjecting these two genotypes to chilling temperature (4 °C, for a maximum of seven days), bioactive compounds such as withanolide A in the roots and withaferin A in leaves were detected in both genotypes, suggesting the involvement of withanolides in cold tolerance. Moreover, the wild genotype showed a higher accumulation of marker withanolides than the cultivated one, which could mean that plants may not produce relevant bioactive compounds when out of their natural habitat, which is discussed later.

Glucosylated terpenoids (e.g., some sesquiterpenes) are another group of PSM involved in cold stress tolerance. Zhao et al. [111] reported the accumulation of glucosylated sesquiterpene and nerolidol glucoside (i.e., catalyzed by plant glycosyltransferase, UGT91Q2) in tea plants (Camellia sinensis) in response to cold stress (freezing temperature, −5 °C, for 4 h). The accumulation of nerolidol glucoside was directly proportional to the expression‎ level of UGT91Q2, indicating that cold stress induces glycosylation in tea. Moreover, the ROS-scavenging ability of nerolidol glucoside was significantly higher than nerolidol, thus increasing cold tolerance in tea.

3.2. 저온 스트레스가 PSM에 미치는 영향

저온 스트레스 또는 저온 스트레스는

영하(20°C 미만) 또는 영하(0°C 미만)의 온도이며,

식물의 성장과 발달에 악영향을 미칩니다.

아열대 및 열대 지역에서 자라는 식물은

온대 종보다 저온 스트레스에 더 민감합니다[209].

식물의 저온 스트레스 내성은 스트레스 방어 유전자의 선택적 발현을 통해 이루어지며, 이는 Chinnusamy 등[210]에 의해 검토되었습니다. 예를 들어, 전 등[106]은 6일령의 타르타르 메밀(파고피룸 타르타리쿰)을 저온 노출(4°C에서 다양한 기간 동안) 후 전사체와 대사산물을 조사하여 페닐프로파노이드 생합성 전사체의 상향 조절과 항산화제인 안토시아닌과 프로안토시아니딘의 상당한 축적을 관찰했습니다(표 1) [107]. 두 가지 포도나무 품종(내한성 - Maerchal Foch, 내한성 - Kiszmisz Luczistyj)을 180-200 μm/(m2s) 조도에서 14시간 광기간 동안 10/7 °C 주야간 주기에 노출했을 때, 내한성 품종은 Folin-Ciocalteu의 시약을 사용하여 평가했을 때 총 페놀 화합물 함량이 더 높았습니다 [211]. 그 후 두 품종의 잎 추출물의 항산화 능력을 DPPH(2,2-디페닐-1-피크릴히드라질) 자유 라디칼 소거 분석법으로 테스트한 결과, 내한성 품종의 잎이 더 나은 활성을 나타냈습니다.

저온 스트레스를 받는 식물에서 PSM의 역할에 대한 또 다른 흥미로운 예로는 생물학적 활성 위타놀드의 주요 공급원인 약용 식물인 인도 인삼(Withania somnifera L.)이 있습니다. Mir 등[108]은 두 가지 유전자형(AGB002-야생 유전자형 및 AGB025-재배 유전자형)에서 저온 스트레스에 반응하는 위타놀드의 축적을 연구했습니다. 이 두 유전자형을 저온(4°C, 최대 7일간)에 노출시킨 결과, 두 유전자형 모두에서 뿌리에서 위타놀리드 A와 잎에서 위타페린 A와 같은 생리 활성 화합물이 검출되어 위타놀리드가 내한성에 관여함을 시사합니다. 또한 야생 유전자형은 재배 유전자형보다 마커 위타놀리드의 축적이 더 높았는데, 이는 식물이 자연 서식지를 벗어났을 때 관련 생리 활성 화합물을 생산하지 못할 수 있음을 의미할 수 있으며, 이에 대해서는 나중에 설명합니다.

글루코실화된 테르페노이드(예: 일부 세스키테르펜)는 저온 스트레스 내성에 관여하는 또 다른 PSM 그룹입니다. Zhao 등[111]은 저온 스트레스(동결 온도, -5°C, 4시간 동안)에 반응하여 차 식물(동백나무)에서 글루코실화된 세스키테르펜과 네롤리돌 글루코사이드(즉, 식물 글리코실 트랜스퍼라제, UGT91Q2에 의해 촉매)의 축적을 보고했습니다. 네롤리돌 글루코사이드의 축적은 UGT91Q2의 발현 수준에 정비례하여 저온 스트레스가 차에서 당화를 유도한다는 것을 나타냅니다. 또한 네롤리돌 글루코사이드의 ROS 제거 능력은 네롤리돌보다 유의하게 높았으며, 따라서 차의 내한성을 증가시켰습니다.

3.3. Effects of Drought Stress on PSMs

Climate change is expected to alter precipitation patterns and results in drought stress (water deficit) in some plants. Drought stress is considered major abiotic stress that impedes metabolism [212,213] and leads to changes in plants at the morphological, physiological, biochemical, metabolic, and transcriptional levels. ROS formation is one drought stress effect, which damages cellular components, including proteins, lipids, and nucleic acids [214,215]. Accumulation of flavonoids such as flavonols and anthocyanins is essential in protecting against abiotic stresses, including drought stress, but the mechanism of action is poorly understood [216]. For example, concentrations of antioxidant flavonols epigallocatechin gallate, epicatechin, and epicatechin gallate increase in the leaves of Cistus clusii under drought stress, reaching a maximum after 30 days of exposure [120,217]. However, the efficacy of photosystem II (PSII) and lipid peroxidation remained unchanged. Under drought stress, PSII in the cotton (Gossypium hirsutum) also remained unaffected [218]. Nakabayashi et al. [216,219] also obtained a similar result (increasing flavonols and anthocyanins) under drought stress in the aerial parts of Arabidopsis thaliana (wild type, Col-0) and confirmed that overaccumulation of flavonoids is key to drought tolerance. There was also a drastic increase in the concentrations of glycosides of kaempferol, quercetin, and cyanidin along with drought stress marker metabolites (proline, raffinose, and galactinol). Excessive accumulation of anthocyanins protects plants against drought stress [219], and anthocyanins are thought to be more robust antioxidants due to their higher level of hydroxylation [220]. A few other studies [221,222] have reported similar observations, i.e., increased accumulation of anthocyanins in plants under drought. Drought stress in Amaranthus tricolor genotype VA3 increased concentrations of at least 16 phenolic compounds, including six hydroxybenzoic acids, seven hydroxycinnamic acids, three flavonoids, and a new phenolic acid, trans-cinnamic acid (Table 1) [112]. In tea plants, fulvic acid is the primary driver of tolerance against drought stress by enhancing ascorbate and glutathione metabolism and promoting flavonoids biosynthesis [223]. More examples and patterns of biochemical changes induced by drought stress in plants are given in Table 1.

3.3. 가뭄 스트레스가 PSM에 미치는 영향

기후 변화는 강수 패턴을 변화시키고

일부 식물에서 가뭄 스트레스(물 부족)를 초래할 것으로 예상됩니다.

가뭄 스트레스는 신진대사를 방해하는 주요 비생물적 스트레스로 간주되며[212,213] 형태적, 생리적, 생화학적, 대사적, 전사적 수준에서 식물에 변화를 일으킵니다. ROS 형성은 단백질, 지질, 핵산을 포함한 세포 성분을 손상시키는 가뭄 스트레스 효과 중 하나입니다[214,215]. 플라보놀과 안토시아닌과 같은 플라보노이드의 축적은 가뭄 스트레스를 포함한 비생물학적 스트레스로부터 보호하는 데 필수적이지만 그 작용 메커니즘은 잘 알려져 있지 않습니다 [216]. 예를 들어, 항산화 플라보놀 에피갈로카테킨 갈레이트, 에피카테킨 및 에피카테킨 갈레이트의 농도는 가뭄 스트레스를 받는 시스터스 클루시 잎에서 증가하여 노출 30일 후에 최대에 도달합니다 [120,217]. 그러나 광합성 시스템 II(PSII)와 지질 과산화의 효능은 변하지 않았습니다. 가뭄 스트레스 하에서 목화(고시피움 히르수툼)의 PSII도 영향을 받지 않았습니다 [218]. 나카바야시 등[216,219] 또한 애기장대(야생형, Col-0)의 공중부에서 가뭄 스트레스 하에서 유사한 결과(플라보놀과 안토시아닌 증가)를 얻었으며 플라보노이드의 과잉 축적이 가뭄 내성의 핵심임을 확인했습니다. 또한 가뭄 스트레스 표지 대사산물(프롤린, 라피노스, 갈락티놀)과 함께 켐페롤, 케르세틴, 시아니딘의 배당체 농도가 급격히 증가했습니다. 안토시아닌의 과도한 축적은 가뭄 스트레스로부터 식물을 보호하며[219], 안토시아닌은 더 높은 수준의 하이드 록실화로 인해 더 강력한 항산화 물질로 생각됩니다 [220]. 다른 몇몇 연구[221,222]에서도 유사한 관찰, 즉 가뭄 시 식물에서 안토시아닌 축적이 증가한다고 보고했습니다. 아마란투스 삼색 유전자형 VA3의 가뭄 스트레스는 6개의 하이드 록시 벤조산, 7개의 하이드 록시 신남산, 3개의 플라보노이드 및 새로운 페놀산 인 트랜스 신남산을 포함하여 최소 16 개의 페놀 화합물의 농도를 증가 시켰습니다 (표 1) [112]. 차나무에서 풀빅산은 아스코르브산과 글루타치온 대사를 강화하고 플라보노이드 생합성을 촉진함으로써 가뭄 스트레스에 대한 내성을 높이는 주요 원동력입니다 [223]. 식물의 가뭄 스트레스로 인한 생화학적 변화의 더 많은 예와 패턴은 표 1 에 나와 있습니다.

3.4. Effects of Ultraviolet (UV) Radiation on PSMs

Plants respond to excessive ultraviolet radiation (UV) both morphologically and physiologically. UV radiation is known to trigger a wide range of responses in plant cells, mainly by UV-B (280–320 nm) and less by UV-A (315–400 nm). Plants’ response to UV stress depends on their perception, signal transduction mechanism, and influence of gene expression‎ [224]. Other environmental factors also influence response to UV-B stress in plants as UV radiation indirectly damages the photosynthetic apparatus by generating ROS [225]. Thus, plants have developed a mechanism to protect against UV radiation and allow photosynthetically active radiation (PAR) to reach mesophyll and palisade tissues in order to enable photosynthesis. Synthesizing UV-absorbing flavonoids is one mechanism to mitigate photoinhibition and photooxidative damage by either reducing UV penetration or quenching ROS. Flavonoids can absorb radiation in the UV region of the spectrum; thus, these compounds are responsible for filtering UV light in plants [226]. Unlike other lights of different wavelengths, UV-B radiation can damage DNA and chloroplasts, particularly photosystem II (PSII) and modify or inhibit gene expression‎ due to its high energy, and they are absorbed by a wide range of molecules [227]. When Stapleton and Walbot [226] investigated DNA damage in maize plants exposed to UV-C or UV-B radiation at a dose of 6000 J/m2, maize plants with flavonoids, primarily anthocyanins, suffered less DNA damage than maize plants deficient in flavonoids. Flavonoids with a catechol group in their B-ring skeleton (e.g., quercetin derivatives) are best known to protect photosynthetic tissues from such oxidative damage [228]. Moreover, exposure to excess UV-B radiation causes increased synthesis of stronger antioxidants such as dihydroxy B-ring-substituted flavonoids (e.g., quercetin and luteolin glycosides) (Figure 5) and less effective antioxidant flavonoids such as kaempferol or apigenin glycosides [229,230]. As a response to UV irradiation, the concentrations of quercetin flavonoids increase in Brassica napus [156] and Fagopyrum esculentum [163]. The concentration of antioxidative flavonoids increased in Kalanchoe pinnata when exposed to UV-B radiation compared to ordinary white light [231]. When Del Valle et al. [225] investigated the effects of UV radiation in Silene littorea, UV exposure increased the concentrations of protective phenolic compounds but affected its reproductive efficacy. UV-B radiation modifies gene expression‎, but their underlying molecular mechanism is not well understood, unlike other phytochrome and blue/or UV-A. Herrlich et al. [232] attribute plant response to UV-B stress mainly to damage caused to cell membranes and DNA. The multiple roles of flavonoids, including photoprotection and the effects of stress on flavonoid biosynthesis, are reviewed elsewhere [52,54].

3.5. Effects of Ozone on PSMs

Ozone (O3) in the lower atmosphere (troposphere) acts as a greenhouse gas and is phototoxic to plants [233]. It is usually produced by reactions between primary pollutants (such as carbon oxides, sulphur oxides, nitric oxides, and hydrocarbons) catalyzed by sunlight. Although O3 is neither a free radical nor a ROS, its strong oxidizing properties enable it to react with biomacromolecules, including lipids, proteins, nucleic acids, and carbohydrates [234]. Generally, O3 enters through stomata and damages leaf tissues, mainly in the upper (adaxial) layers resulting in chlorosis and lesions. Physiologically, exposure to O3 impairs stomatal function (dysfunction of transpiration and water use efficiency) and reproductive development, CO2 assimilation, and subsequently photosynthetic activity. In snap bean (Phaseolus vulgaris), exposure to an ambient concentration of O3 (≤150 ppb, 1 h) [along with water stress (≤15%)] induces sluggishness in stomatal closure, subsequently causing more significant loss of leaf surface water [235].

In addition to changes in plant physiological functions, O3 triggers pathways responsible for producing defensive molecules, such as flavonoids. When Mao et al. exposed soybean leaves to elevated O3 (110 ± 10 nmol mol−1 for 8 h daily, for 54 days), the concentrations of rutin, quercetin, and total flavonoids increased significantly [236]. Ozone also enhances the activity of enzymes involved in flavonoid biosynthesis. Plants fumigated with O3 show increased activities of phenylalanine-ammonium lyase (PAL), and chalcone synthase (CHS) enzymes involved in phenylpropanoid and flavonoid biosynthesis pathways [237] and subsequently produce protective compounds that can scavenge ROS [56]. The general phenylpropanoid pathway and flavonoid biosynthesis pathways are outlined in Figure 6 below. These pathways, in turn, contribute significantly towards plant defense response by producing protective phenolic compounds such as condensed tannins and flavonoids that can scavenge ROS [57]. For instance, when Arabidopsis thaliana is exposed to O3 (300 ppb daily for 6 h), PAL mRNA levels increase 3-fold compared to their control plants [238]. Similarly, O3 treatment (200 nL/L for 10 h) increases both PAL and CHS activities resulting in a 2-fold increase of total leaf furanocoumarins and flavone glycosides in parsley (Petroselinum crispum) [239]. Lignin deposition in O3 exposed leaves is also linked to increased PAL activity [240], whereas in sage (Salvia officinalis), both PAL and PPO (phenol oxidase) activities were suppressed after 24 h exposure to O3 [241]. However, rosmarinic acid synthase (RAS) activity is accompanied by the increased transcription level of genes (e.g., RAS) encoding biosynthesis enzymes, suggesting that the sage plant mediates oxidative damage through synthesizing phenolic compounds.

Figure 6.

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General phenylpropanoid pathway and flavonoid biosynthesis (adapted from [247,248]. Solid arrows represent single enzymatic reaction; dashed arrows represent multiple sequential reactions. Enzymes involved: PAL—phenylalanine ammonia lyase; CHS—chalcone synthase; STS—stilbene synthase; CHR—chalcone reductase.

Studies have shown that plant chemical responses to O3 exposure variably depend on the O3 concentration [242]. Ozone alone enhances the production of phenolic compounds more significantly than in response to the increased CO2 concentration, while the combination of these two factors resulted in higher diterpenes, but not mono- and sesquiterpene, synthesis in plants [243]. However, some experiments showed contrasting results from O3 fumigation. Leaves of Ginkgo biloba, upon fumigation with an elevated level of O3, increased the concentrations of terpenes (Table 1), but phenolics decreased [152]. Ozone also enhances the accumulation of salicylic acid (SA) in plant tissues; for instance, in the tobacco plant (Nicotiana tabacum), emission of SA-derived methyl salicylate increases upon exposure to O3 [244,245]. In Arabidopsis, SA accumulation is necessary for forming O3-induced mRNAs, such as PAL and pathogenesis-related protein 1 (PAR1) transcripts [245]. Nevertheless, some plants (such as tobacco plants) do not require SA accumulation to form PAL transcripts [246]. These examples suggest that O3 induces at least two signaling pathways, the SA-dependent pathway associated with pathogen defense response and the SA-independent pathway in the protective response to O3.

Isoprene in tree foliage is known to protect foliage from oxidative stress. For instance, when Loreto et al. [204] applied isoprene (2–3 ppm) exogenously to tobacco and birch leaves fumigated with O3 (300 ppb), photosynthesis was consistent throughout the treatment period with the less accumulation of ROS compared to their fosmidomycin-treated control (showed more ROS accumulation and decreased rate of photosynthesis). Moreover, after three days of O3 treatment, they observed that areas of leaves treated with isoprene were intact, suggesting that isoprene protects photosynthetic tissues and stabilizes the thylakoid membrane. Isoprene protects photosynthesis in those plants exposed to acute thermal and O3 stress through antioxidative action (quench H2O2) and preventing membrane lipid peroxidation. For instance, leaves of Phragmites australis for which their endogenous isoprene production was inhibited by applying fosmidomycin become more sensitive to O3 stress than isoprene-producing leaves [204].

Exposure to high O3 concentration causes VOC emission, but at chronic O3 level, it modifies compositions of BVOCs, consequently affecting tri-trophic interactions and weakening plants’ response to arthropod attack [245,249]. During such situations, isoprenoids (mainly hemiterpenes, monoterpenes, and sesquiterpenes) are synthesized by plants to tolerate O3-induced damages. Hemiterpene is an example of an isoprenoid released in the leaves, as it can protect photosynthetic apparatus and scavenge O3 by-products and ROS due to its antioxidative activity [204]. The effect of O3 on alkaloid biosynthesis remains less elucidated, but polyamines in plants, which is an important alkaloid precursor, are correlated to O3 tolerance [234]. Polyamines in plants possess a wide array of physiological functions [240] in addition their involvement in response to both abiotic and biotic stresses [250].

4. Reported Pharmacological Properties of PSMs Present in Plants Affected by Ex Situ Abiotic Stresses

Plant protective secondary metabolites are diverse in structure and biological properties, and they have been continuously exploited for pharmaceutical, nutraceutical, and cosmetic uses [251] (Figure 7). Flavonoids and other phenolic compounds are predominant among secondary metabolites produced in response to climatic/or abiotic stress (Table 1). Flavonoids confer protection against inflammation, allergy, and bacterial infections [252]. Flavonols (or 3-hydroxy flavones), one of the main subclass of flavonoids, are apparent antioxidants in stressed plants, and they are known to prevent nuclear DNA damage by free radicals like H2O2 [253]. Flavonols are polyaromatic secondary metabolites with three rings, and many of them are bioactive. Many flavonoids possess antiviral properties. For instance, the hydroxy (OH) group in the ring-C of flavonols makes them more effective against herpes simplex virus type I than flavones [254]. Fisetin is another example of an active flavonoid produced by plants under oxidative stress, preventing membrane lipid peroxidation, DNA damage, and protein carbonylation [247]. Fisetin showed numerous biological activities such as protection against cell death from oxidative stress, growth, and maintenance of nerve cells (primary cortical neurons from a rat) [248,255]. Fisetin suppresses many inflammatory pathways, including Nuclear Factor-kappa B (NF-kB) pathway, helping prevent cancerous growth [256,257]. Similarly, Hussain et al. [258] also observed the protective effect of fisetin against smoke-induced oxidative stress and inflammation in rat lungs. Plant UV filters, kaempferol, and quercetin are a few other examples of bioactive flavonoids. Kaempferol is an anti-inflammatory [259], chemo-protective [260], and cardio-protective [261]. Polyphenolic resveratrol is one of the essential stilbene phytoalexin produced by a plant’s defense mechanism, and it possesses antioxidant, anticancer, and anti-estrogenic properties [262]. The immunoinhibitory compound, calycopterin isolated from the medicinal plant Dracocephalum kotschyi [168], was elevated upon UV irradiation in Gnaphalium luteo-album [167]. Tanshinones are other examples of bioactive phenols. In response to severe drought stress, their concentration in the Salvia miltiorrhiza increases, including tanshinone I and tanshinone IIA by 182% and 322%, respectively, compared to 148% under the moderate drought stress [139]. Tanshinones are known for their anti-inflammatory, antioxidant, and anticancer properties [263].

Figure 7.

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Chemical structure of compounds known to accumulate in plants under various abiotic stress conditions.

Nitrogen-containing compounds, alkaloids, are another group of secondary metabolites widely produced in plants for defense, and they are known to exhibit diverse biological activities, including anti-inflammatory, anti-malarial, and anticancer activities [264]. The fungistatic activity of α-tomatine (Solanum and Lycopersicon species) in Fusarium oxysporum f. lycopersici (tomato wilt) was the first bioactive alkaloid reported in 1945 by Irving et al. [69]. Alkaloids and their precursors accumulate more in plants when exposed to various stress factors. For example, Catharanthus roseus, when exposed to UV-B radiation, synthesizes more indole alkaloids and precursors of vinblastine and vincristine increase in hairy roots [265]. These alkaloids inhibit cell mitosis by destroying microtubules of the mitotic apparatus, blocking cancer cell division [266]. Bioactive alkaloids accumulate in response to high temperature, drought, and UV-B stresses (Table 1). Indole alkaloid vindoline from Catharanthus roseus (which increases in response to UV-B) showed anti-diabetic (reduces fasting blood glucose level) and anti-inflammatory (reduces pro-inflammatory cytokines, TNF- α and IL-6) properties [99].

The number of structurally determined specialized plant terpenes exceeds 105, including >12,000 diterpenoids [267]. Plant terpenoids are diverse and have been a valuable source of medicinal discoveries because terpenoids are natural NF-kB signaling inhibitors with anti-inflammatory and anti-cancer properties [268]. Examples include monoterpenes (e.g., (−)-menthol and cannabinoids); sesquiterpenes (e.g., artemisinin and thapsigargin); diterpenes (e.g., paclitaxel and ingenol mebutate) and triterpenes found in floral and vegetative parts; triterpenoids; and carotenoids (e.g., steroidal alkaloids, cardenolides, and bixin) (Figure 7). Other compounds are partially derived from a terpene precursor, such as monoterpenoid alkaloids (e.g., strychnine), which are synthesized in part from secologanin (Figure 7), a member of the widespread class of iridoid monoterpenes [269].

5. Biodiscovery Potential of Plants Growing under Ex-Situ Abiotic Stresses

Natural products, including PSMs, have been a significant source of medicines. According to Newman and Cragg, between 1981 and 2010, 1073 small molecules (mol. wt. < 1000 Da) were approved as new chemical entities, out of which more than half were from natural products [270]. An additional 321 small molecules were reported in another review published in September 2019 [271]. According to Butler et al. [272], in their review covering natural products-derived drugs between 2008–2013, 25 drugs were launched since 2008, and additional 31 compounds were in the last stage clinical trial (phase III). According to the database on www.clinicaltrials.gov (accessed 5 September 2021), four compounds have advanced to phase-IV clinical trial, sixteen have completed phase-III, nine have not yet completed phase-III, and two compounds have been withdrawn. The four compounds that have advanced to clinical trial phase-IV are oritavancin (anti-bacterial), ipragliflozin, tofoglifozin (anti-diabetic, type II diabetes), and vorapaxar (anti-thrombotic) [272]. Recently, pharmaceutical industries and researchers have renewed their interest in PSMs due to advancements in cutting-edge technology, including various chromatography and high-resolution spectroscopy tools and omics platforms [273].

Interestingly, not many PSMs were subjected to clinical trials. The reasons are varied. One of the continuing challenges for drug discovery from plant sources is obtaining enough sample extracts and compounds for testing in vitro and in vivo disease models. This bottleneck is heightened for species in the IUCN red list of threatened or endangered species prohibited for large sample collection, even if they show biological hits. While cultivating pharmaceutically interesting plant species may be a solution, it is not always possible to culture the organism outside its natural habitat. Even when possible, relevant natural products may not be produced outside their natural habitat [273]. Alternatively, plants affected by climate change could be a potential source of novel drug leads, considering the vast diversity of phytochemicals produced by them in response to various abiotic stress conditions (Table 1).

Climate change rapidly and severely affects plant ecosystems; for instance, mountaintop ecosystems are sensitive to small shifts in temperature and precipitation patterns [274]. Several studies on the mountaintops of the Asia-Pacific region [275], Oceania [276], and Europe [277] have reported accelerated plant ecological responses, including distribution, ecophysiology, and interaction with other organisms due to climatic changes. In overcoming climate change-induced/or abiotic stress and finding an optimal climate niche, plants produce diverse PSMs, which could be of pharmaceutical interest. For example, the synthesis of plant terpenoids increases under heat, cold, and O3 stress, and the yield of many biologically active compounds also increases in plants grown in simulated environments of various abiotic stress conditions (Table 1). Abiotic stresses elicit bioactive compound synthesis [278], such as phenylpropanoids biosynthesis (mainly through shikimate pathway), causing an accumulation of compounds with defense or signaling functions (e.g., phenolics, flavonoids, and alkaloids) [279]. Similarly, it is reported that drought stress increases the concentration of camptothecin (anticancer alkaloid) in Camptotheca acuminata [116,117] and morphine (analgesic) concentrations in Papaver somniferum. The increased accumulation of PSMs in response to stress indicates that there may be novel bioactive alkaloid(s) in climate change-affected plants awaiting discovery. Abiotic stress factors under conditioned environment can potentially improve the yield of bioactive compounds in plants.

6. Conclusions

Plants constantly interact with the environment, and climate change has already impacted their diversity, growth, and survival. In order to minimize the impact of various climate change-related stresses (such as warming due to increased greenhouse gas emission, drought, cold, ozone-layer depletion, and harmful UV-radiation), plants produce diverse defense secondary metabolites, mainly phenolic and nitrogen-containing compounds. The biosynthesis of defense compounds in plants (including medicinal plants) is often upregulated, and these compounds are associated with various pharmacological properties, suggesting that plants affected by climate change may be a rich resource for drug discovery. However, most of these studies were conducted in simulated/or artificial environments. Thus, it would be interesting if more such studies (defense compounds produced by plants in response to climatic stress and their bioactivity) could be conducted by using plant samples from their natural habitats that are already challenged by the various climatic stresses.

It is difficult to access various natural products bound by legislation and societal restrictions, including plants, for drug discovery research, particularly plants associated with indigenous knowledge. This limitation remains a considerable challenge for those working with medicinal plants. Other wild plants exposed to various climatic/or abiotic stresses would be an alternative option for drug discovery researchers. Another obstacle in the drug discovery process is obtaining adequate compounds for further biological tests (both in vitro and in vivo). Bioactive compounds increase their concentration in plants exposed to stress, for example, withanolides in Indian ginseng (Withania somnifera) increases in response to cold stress. Culturing plant tissues of interest at a large scale under a conditioned environment using various abiotic stresses can potentially improve the yield of bioactive compounds from plants. Thus, plant tissue culture would be another platform for researchers and pharmaceutical industries to upscale the production of valuable phytochemicals under duress of climate change factors.

6. 결론
식물은 환경과 끊임없이 상호작용하며 기후 변화는 이미 식물의 다양성, 성장, 생존에 영향을 미치고 있습니다. 온실가스 배출 증가로 인한 온난화, 가뭄, 추위, 오존층 파괴, 유해한 자외선 등 다양한 기후 변화 관련 스트레스의 영향을 최소화하기 위해 식물은 주로 페놀과 질소 함유 화합물 등 다양한 방어 이차 대사산물을 생산합니다. 식물(약용 식물 포함)에서 방어 화합물의 생합성은 종종 상향 조절되며, 이러한 화합물은 다양한 약리학적 특성과 관련이 있어 기후 변화의 영향을 받는 식물이 신약 개발을 위한 풍부한 자원이 될 수 있음을 시사합니다. 그러나 이러한 연구의 대부분은 시뮬레이션 또는 인공 환경에서 수행되었습니다. 따라서 이미 다양한 기후 스트레스를 받고 있는 자연 서식지의 식물 샘플을 사용하여 이러한 연구(기후 스트레스에 대응하여 식물이 생성하는 방어 화합물과 그 생리 활성)를 더 많이 수행할 수 있다면 흥미로울 것입니다.

신약 개발 연구를 위해 식물을 포함한 다양한 천연물, 특히 토착 지식과 관련된 식물은 법률 및 사회적 제약에 묶여 접근하기 어렵습니다. 이러한 제한은 약용 식물을 다루는 사람들에게 여전히 상당한 도전으로 남아 있습니다. 다양한 기후적/비생물적 스트레스에 노출된 다른 야생 식물은 신약 개발 연구자들에게 대안이 될 수 있습니다. 신약 개발 과정의 또 다른 장애물은 추가 생물학적 테스트(시험관 및 생체 내)를 위한 적절한 화합물을 확보하는 것입니다. 예를 들어 인도 인삼(위타니아 솜니페라)의 위타놀리드는 추위 스트레스에 반응하여 증가하는 등, 스트레스에 노출된 식물에서는 생리 활성 화합물의 농도가 증가합니다. 다양한 비생물학적 스트레스를 사용하여 조건화된 환경에서 관심 있는 식물 조직을 대규모로 배양하면 식물에서 생리 활성 화합물의 수율을 잠재적으로 향상시킬 수 있습니다. 따라서 식물 조직 배양은 연구자와 제약 업계가 기후 변화 요인의 압박 속에서 귀중한 파이토케미컬의 생산을 확대할 수 있는 또 다른 플랫폼이 될 수 있습니다.

Author Contributions

Conceptualization, P.W. and K.Y.; writing—original draft preparation, K.Y.; writing—review and editing, P.W., D.C. and E.R.; supervision, P.W.; funding acquisition, P.W. and D.C. All authors have read and agreed to the published version of the manuscript.

Funding

This review was funded by James Cook University Postgraduate Research Scholarship (JCUPRS) to Karma Yeshi; NHMRC Ideas grant (APP1183323) to Phurpa Wangchuk and Darren Crayn; and research grants from the Ian Potter Foundation and the Wet Tropics Management Authority to Darren Crayn.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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