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Polyphenols in Plants: Structure, Biosynthesis, Abiotic Stress Regulation, and Practical Applications (Review)

by 

Natalia V. Zagoskina

 1,*

,

Maria Y. Zubova

 1

,

Tatiana L. Nechaeva

 1

,

Varvara V. Kazantseva

 1,

Evgenia A. Goncharuk

 1

,

Vera M. Katanskaya

 1,

Ekaterina N. Baranova

 2,3

 and

Maria A. Aksenova

 1

1

K.A. Timiryazev Institute of Plant Physiology, Russian Academy of Sciences, 127276 Moscow, Russia

2

N.V. Tsitsin Main Botanical Garden of Russian Academy of Sciences, 127276 Moscow, Russia

3

All Russia Research Institute of Agricultural Biotechnology, Russian Academy of Agricultural Sciences, 127550 Moscow, Russia

*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(18), 13874; https://doi.org/10.3390/ijms241813874

Submission received: 17 August 2023 / Revised: 5 September 2023 / Accepted: 7 September 2023 / Published: 9 September 2023

(This article belongs to the Special Issue Advances in the Physiology of Primary and Secondary Plant Metabolism under Abiotic and Biotic Stress)

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Abstract

Phenolic compounds or polyphenols are among the most common compounds of secondary metabolism in plants. Their biosynthesis is characteristic of all plant cells and is carried out with the participation of the shikimate and acetate-malonate pathways. In this case, polyphenols of various structures are formed, such as phenylpropanoids, flavonoids, and various oligomeric and polymeric compounds of phenolic nature. Their number already exceeds 10,000. The diversity of phenolics affects their biological activity and functional role. Most of their representatives are characterized by interaction with reactive oxygen species, which manifests itself not only in plants but also in the human body, where they enter through food chains. Having a high biological activity, phenolic compounds are successfully used as medicines and nutritional supplements for the health of the population. The accumulation and biosynthesis of polyphenols in plants depend on many factors, including physiological–biochemical, molecular–genetic, and environmental factors. In the review, we present the latest literature data on the structure of various classes of phenolic compounds, their antioxidant activity, and their biosynthesis, including their molecular genetic aspects (genes and transfactors). Since plants grow with significant environmental changes on the planet, their response to the action of abiotic factors (light, UV radiation, temperature, and heavy metals) at the level of accumulation and composition of these secondary metabolites, as well as their metabolic regulation, is considered. Information is given about plant polyphenols as important and necessary components of functional nutrition and pharmaceutically valuable substances for the health of the population. Proposals on promising areas of research and development in the field of plant polyphenols are presented.

요약

페놀 화합물 또는 폴리페놀은 

식물에서 이차 대사 과정에서 가장 흔하게 발생하는 화합물 중 하나입니다. 

이 화합물의 생합성은 

모든 식물 세포의 특징이며, 

시키메이트와 아세테이트-말론산 경로의 참여로 이루어집니다. 

이 과정에서 

페닐프로파노이드, 플라보노이드, 그리고 

다양한 올리고머 및 폴리머 화합물과 같은 다양한 구조의 폴리페놀이 형성됩니다. 

그들의 수는 이미 10,000개를 초과합니다. 

페놀류의 다양성은 

그들의 생물학적 활동과 기능적 역할에 영향을 미칩니다. 

대부분의 대표 물질은 식

물뿐만 아니라 먹이 사슬을 통해 인체에 유입되는 

활성 산소와의 상호 작용을 특징으로 합니다. 

생물학적 활성이 높은 페놀 화합물은 

인구의 건강을 위한 의약품 및 영양 보충제로 성공적으로 사용되고 있습니다. 

식물에서 폴리페놀의 축적과 생합성은 

생리적-생화학적, 분자-유전적, 환경적 요인을 포함한 여러 요인에 의해 좌우됩니다. 

이 리뷰에서는 

다양한 종류의 페놀 화합물의 구조, 항산화 활성, 생합성에 관한 최신 문헌 데이터를 

분자 유전적 측면(유전자와 전이 인자)을 포함하여 제시합니다. 

식물은 지구상의 환경 변화에 따라 성장하기 때문에, 

이차 대사 산물의 축적 및 구성 수준에서 비생물적 요인(빛, 자외선, 온도, 중금속)의 작용에 대한 반응과 대사 조절이 고려됩니다. 기능성 영양의 중요하고 필수적인 구성 요소이자 인구의 건강에 중요한 약학적으로 가치 있는 물질인 식물 폴리페놀에 대한 정보가 제공됩니다. 식물 폴리페놀 분야의 유망한 연구 및 개발 분야에 대한 제안이 제시됩니다.

Keywords: 

phenolic compounds; phenylpropanoids; flavonoids; antioxidant activity; environmental factors; regulation; health care

1. Introduction

A unique characteristic of plants, along with photosynthesis, is their ability to form various low-molecular-weight specialized (secondary) compounds that do not participate in primary metabolism [1,2]. The primary metabolites are crucial for plant growth and development, whereas secondary metabolites are viewed as essential components for their interaction with the environment [3,4].

The spectrum of synthesized secondary metabolites in plants is diverse. The main representatives are terpenes, alkaloids, cyanogenic glucosides, and polyphenols [1,4].

Polyphenols or phenolic compounds (PCs) are considered to be among the most preval‎ent secondary metabolites, synthesized in all plant cells [5,6]. Significant progress has been made to date in establishing their structure and chemical properties [7,8]. The biosynthesis of PCs is extensively studied, and the key enzymes participating in this process are identified [7,9,10]. Due to transcriptome research, there are data on genes that determine cells’ ability to produce these compounds [11,12], along with numerous molecular markers that are valuable for identifying phenol-producing plants [13].

Formerly, in the 20th century, PCs were considered only as a mechanism to eliminate high-carbon components from metabolism. However, now, their significant contribution to plant cell functionality is beyond doubt [3]. The production of these metabolites is essential for plant growth and development and protection against various biotic and abiotic factors [4,6,7].

The accumulation of PCs in the early stages of plant growth is known well [14]. The correlation between its formation and the process of photosynthesis [15], auxin metabolism [16], and cell protection against various stressors [7,9,17] has been proved. The latter characteristic is associated with the antioxidant capacity of PCs, which is determined by their chemical structure [7,18]. This aspect of the functional role of these specialized metabolites commands significant attention from researchers due to the broad-ranging activity of these metabolites within the human body. The PCs’ capillary-strengthening, antibacterial, antiviral, antitoxic, and neurodegenerative effects are known [19,20].

Plant-derived PCs, frequently referred to as bioflavonoids, are increasingly used as therapeutic pharmaceutical agents for treating diseases of various etiologies [4,21,22]. Despite the considerable number of publications regarding plant-derived PCs, their structure, biosynthesis, and function require further research.

This concerns the study of the structural diversity of these metabolites and their properties. A greater “detailing” of PCs’ biosynthesis is needed, including genes and transcription factors that ensure its functioning. Ideas about the influence of various environmental factors on the accumulation of PCs in plants are still rather contradictory and ambivalent. However, their study and eval‎uation are very important for agricultural crops and medicinal plants, which are successfully used as producers of biologically active compounds and nutraceuticals in the food industry and pharmacology.

In our review, we briefly present the current state of research on the structure of various PCs, their properties (mainly antioxidant activity), and the main stages of biosynthesis, including genes and transcription factors. In addition, we present recent data on the regulatory effect of various abiotic environmental factors (light, UV radiation, temperature, and heavy metals) on the accumulation of PCs in plants. Since these are some of the plant metabolites actively used in pharmacology, there is a small section on their use in medicine. The important fundamental and practical significance of PCs allowed us to consider the prospects for further research on these unique plant metabolites.

1. 서론

식물의 독특한 특징 중 하나는

광합성과 함께 1차 대사에 관여하지 않는

다양한 저분자량 특수(2차) 화합물을 형성하는 능력입니다 [1,2].

1차 대사 산물은

식물의 성장과 발달에 필수적인 반면,

2차 대사 산물은 환경과의 상호 작용에 필수적인 요소로 간주됩니다 [3,4].

식물에서 합성되는 2차 대사 산물의 스펙트럼은

다양합니다.

주요 대표 물질로는

테르펜, 알칼로이드, 시아노겐 글루코사이드, 폴리페놀이 있습니다 [1,4].

폴리페놀 또는 페놀 화합물(PC)은

모든 식물 세포에서 합성되는 가장 널리 퍼진 2차 대사 산물로 간주됩니다 [5,6].

지금까지 폴리페놀의 구조와 화학적 특성을 규명하는 데 상당한 진전이 있었습니다 [7,8]. PC의 생합성은 광범위하게 연구되어 왔으며, 이 과정에 관여하는 주요 효소가 확인되었습니다 [7,9,10]. 전사체 연구 덕분에, 이러한 화합물을 생산하는 세포의 능력을 결정하는 유전자에 대한 데이터가 있습니다 [11,12], 페놀을 생산하는 식물을 식별하는 데 유용한 수많은 분자 표지자 [13]와 함께.

20세기에는 PC가 신진대사 과정에서 탄소 성분을 제거하는 메커니즘으로만 간주되었습니다. 그러나 이제는 식물 세포 기능에 대한 PC의 중요한 기여가 의심할 여지가 없습니다 [3]. 이러한 대사 산물의 생산은 식물 성장과 발달, 그리고 다양한 생물적 및 비생물적 요인으로부터의 보호에 필수적입니다 [4,6,7].

식물 성장의 초기 단계에서 PC의 축적은 잘 알려져 있습니다 [14]. PC의 형성과 광합성 과정 [15], 옥신 대사 [16], 다양한 스트레스 요인에 대한 세포 보호 [7,9,17] 사이의 상관관계가 입증되었습니다. 후자의 특성은 PC의 항산화 능력과 관련이 있으며, 이는 화학 구조에 의해 결정됩니다 [7,18]. 이러한 특수 대사 산물의 기능적 역할에 대한 이 측면은 인체 내에서 이러한 대사 산물의 광범위한 활동으로 인해 연구자들의 상당한 관심을 받고 있습니다. PC의 모세혈관 강화, 항균, 항바이러스, 항독성, 항신경퇴행성 효과는 알려져 있습니다 [19,20].

종종 바이오플라보노이드라고 불리는 식물 유래 PC는 다양한 원인의 질병을 치료하는 치료 약제로 점점 더 많이 사용되고 있습니다 [4,21,22]. 식물 유래 PC에 관한 출판물이 상당히 많음에도 불구하고, 그 구조, 생합성, 기능에 대해서는 추가 연구가 필요합니다.

이는 이러한 대사 산물의 구조적 다양성과 그 특성에 관한 연구와 관련이 있습니다. PC의 생합성을 더 자세히 연구해야 하며, 그 기능을 보장하는 유전자와 전사 인자를 포함해야 합니다. 식물 내 PC 축적에 대한 다양한 환경적 요인의 영향에 대한 아이디어는 여전히 다소 모순적이고 모호합니다. 그러나, 이들의 연구와 평가는 식품 산업과 약리학에서 생물학적 활성 화합물과 기능성 식품의 생산자로 성공적으로 활용되는 농작물과 약용 식물에 매우 중요합니다.

저희의 리뷰에서는 다양한 PC의 구조, 그 특성(주로 항산화 활성), 그리고 유전자와 전사 인자를 포함한 생합성의 주요 단계에 대한 현재 연구 상태를 간략하게 소개합니다. 또한, 식물 내 PC 축적에 대한 다양한 비생물적 환경 요인(빛, 자외선, 온도, 중금속)의 조절 효과에 대한 최근 데이터를 소개합니다. 이것들은 약리학에서 활발하게 사용되는 식물 대사 산물 중 일부이기 때문에, 의학에서의 사용에 대한 작은 섹션이 있습니다. PC의 중요한 기초적, 실제적 중요성을 고려하여, 이러한 독특한 식물 대사 산물에 대한 추가 연구의 전망을 고려할 수 있었습니다.

2. Polyphenols Structure, Properties and Antioxidant Activity

Polyphenols are low-molecular-weight organic substances containing an aromatic (benzene or phenol) ring with one or more hydroxyl groups in their molecule [23]. It can be a simple compound or a complex polymer [24]. They are categorized into various classes and subclasses based on the chemical structure, the number of phenol rings, the position of functional groups, or the carbon skeleton [7,25,26]. Among them, phenol is the simplest and the least common form of PC in plants (Figure 1).

2. 폴리페놀의 구조, 특성, 항산화 작용

폴리페놀은

분자 내에 하나 이상의 수산기가 있는 방향족(벤젠 또는 페놀) 고리를 포함하는

저분자량 유기 물질입니다 [23].

단순한 화합물일 수도 있고,

복잡한 고분자일 수도 있습니다 [24].

이들은 화학 구조,

페놀 고리의 수, 작용기 위치, 또는 탄소 골격에 따라

다양한 등급과 하위 등급으로 분류됩니다 [7,25,26].

그 중에서도 페놀은 식물에서 가장 단순하고 가장 흔하지 않은 형태의 PC입니다 (그림 1).

Figure 1. The structural formula of phenol.

The presence of a single benzene ring along with a one-carbon or three-carbon side chain is a distinguishing feature of hydroxybenzoic and hydroxy-cinnamic acids, respectively (Figure 2). Their general formulas are usually denoted as C6-C1 and C6-C3, respectively [27]. It should be noted that they belong to the class of phenylpropanoids, which are widespread PCs in plants [9,10].

그림 1. 페놀의 구조식.

벤젠 고리 하나와 1개 또는 3개의 탄소 사이드 체인이 함께 존재한다는 것은 각각 히드록시벤조산과 히드록시신남산의 특징입니다(그림 2). 이들의 일반식은 보통 각각 C6-C1과 C6-C3으로 표기됩니다[27]. 이들은 식물에서 널리 분포하는 PC인 페닐프로파노이드 계열에 속한다는 점에 유의해야 합니다[9,10].

Figure 2. Structural formulas of simple polyphenols.

Flavonoid-type PCs exhibit more complex structures, featuring two aromatic rings (labeled as A and B) interconnected by a three-carbon fragment (designated as C) (Figure 3). The general formula for flavonoids is denoted as C6-C3-C6.

그림 2. 단순 폴리페놀의 구조식.

플라보노이드형 폴리페놀은 3개의 탄소 조각(C로 표시)으로 연결된 두 개의 방향족 고리(A와 B로 표시)를 특징으로 하는 더 복잡한 구조를 나타냅니다(그림 3). 플라보노이드의 일반식은 C6-C3-C6으로 표시됩니다.

Figure 3. The structural formula of flavonoids.

Flavonoids are categorized into different subclasses depending on the degree of oxidation (or reduction) of the three-carbon fragment [8,26,27]. The main classes are shown in Figure 4.

그림 3. 플라보노이드의 구조식.

플라보노이드는 3개의 탄소 조각의 산화(또는 환원) 정도에 따라 여러 하위 분류로 나뉩니다 [8,26,27]. 주요 분류는 그림 4에 나와 있습니다.

Figure 4. Main subclasses of flavonoids and some of their representatives.

In addition to the monomeric PCs mentioned earlier, plants also produce oligomeric and polymeric forms. Oligomeric PCs include dimers of phenylpropanoids, flavones, and flavonols, as well as flavan-3-ols and (or) flavan-3,4-diols (depicted in Figure 5). The latter are known as proanthocyanidins [28].

그림 4. 플라보노이드의 주요 하위 분류와 그 대표적 예.

앞서 언급한 단량체 PC 외에도, 식물에서는 올리고머와 폴리머 형태도 생산합니다. 올리고머 PC에는 페닐프로파노이드, 플라본, 플라보놀의 이량체뿐만 아니라 플라반-3-올과 (또는) 플라반-3,4-디올(그림 5에 표시)이 포함됩니다. 후자는 프로안토시아니딘[28]으로 알려져 있습니다.

Figure 5. Structural formulas of dimers from different classes of polyphenols.

Polymers of PCs are tannins, lignin, and melanins. Tannins are classified into hydrolyzable, condensed, thearubigins, and phlorotannins [27,29]. A unique phenolic metabolite formed from phenylpropanoid units is lignin, widely distributed in plant tissues [30,31]. Melanins, somewhat “conditionally” considered PCs since they are primarily formed through the acetate-malonate pathway, have also captured researchers’ interest due to their protective role not only in plants but also in humans [32,33,34]. Figure 6 showcases some of these substances.

그림 5. 폴리페놀의 다른 클래스에서 이량체의 구조식.

폴리페놀의 중합체는 탄닌, 리그닌, 멜라닌입니다. 탄닌은 가수분해성, 응축성, 테아루비긴, 플로로탄닌으로 분류됩니다 [27,29]. 페닐프로판산 단위로 형성된 독특한 페놀 대사 산물은 리그닌으로, 식물 조직에 널리 분포되어 있습니다 [30,31]. 아세테이트-말론산 경로를 통해 주로 형성되기 때문에 “조건부” PC로 간주되는 멜라닌도 식물뿐만 아니라 인간에서도 보호 역할을 하기 때문에 연구자들의 관심을 끌었습니다 [32,33,34]. 그림 6은 이러한 물질 중 일부를 보여줍니다.

Figure 6. Structural formulas of polymeric compounds of phenolic nature.

At present, more than 10,000 PCs have been identified, including both water-soluble and organic-solvent-soluble or insoluble forms [23]. This number continues to grow due to the advancement and implementation of novel analytic research methodologies such as capillary electrophoresis, high-performance liquid chromatography, mass spectrometry, nuclear magnetic resonance, and others [25,26].

The properties of PCs are significantly influenced by their chemical structure [26]. Their ability to form hydrogen bonds (both intermolecular and intramolecular) relies on the degree of hydroxylation of the benzene ring and the position of the hydroxyl group (OH). For instance, meta-substituted diphenols (dioxibenzenes) exhibit significantly greater resistance to oxidation than para- and especially ortho-diphenols [35].

Due to the presence of hydroxyl and carboxyl groups in their molecules, PCs possess the ability to form conjugates with compounds such as sugars, organic acids, plant amines, and others [36]. In this process, glycosidic, methylated, methoxylated, and acylated compounds of a phenolic nature are synthesized. As indicated in earlier studies, flavonoids undergo hydroxylation at positions 3, 5, 7, 2, 3′, 4′, and 5′ (Figure 3). Additionally, glycosidic bonds form at positions 3 or 7, involving glucose, rhamnose, galactose, or arabinose [37]. Some researchers report that during the formation of polyphenolic glycosides, β-glycosidic bonds link one or more sugar residues (monosaccharides, disaccharides, and oligosaccharides) to the hydroxyl group (O-glycosides) or the carbon atom of the aromatic ring (C-glycosides) [38].

According to the literature [25], PCs are characterized by two primary properties: reducing activity, which governs their antioxidant properties and their sensitivity to oxidation, and the binding properties, which are attributed to their metal-chelating activities and their affinity for proteins, including enzymes, transport proteins, and receptors. It is these properties that determine the biological activity of these secondary metabolites in both plant and animal cells.

The biological activity of PCs is frequently eval‎uated through their antioxidant properties [4,39]. These properties stem from their structural composition, comprising an aromatic ring, double bonds, and numerous functional groups [8,37]. PCs interact with reactive oxygen species (ROS) present in cells, which, at high concentrations, induce oxidative stress within them (Figure 7).

그림 6. 페놀계 고분자 화합물의 구조식.

현재, 수용성 및 유기 용매에 용해되거나 용해되지 않는 형태를 포함하여 10,000개 이상의 PC가 확인되었습니다 [23]. 이 숫자는 모세관 전기영동, 고성능 액체 크로마토그래피, 질량 분석법, 핵 자기 공명 등 새로운 분석 연구 방법의 발전과 구현으로 인해 계속 증가하고 있습니다 [25,26].

PC의 특성은 화학 구조에 의해 크게 영향을 받습니다 [26]. 분자간 및 분자 내 수소 결합을 형성하는 능력은 벤젠 고리의 수산화 정도와 수산기(OH)의 위치에 따라 달라집니다. 예를 들어, 메타 치환 디페놀(디옥시벤젠)은 파라-디페놀, 특히 오르토-디페놀보다 산화에 대한 저항성이 훨씬 더 큽니다 [35].

분자 내에 수산기와 카르복실기가 존재하기 때문에, PC는 당, 유기산, 식물성 아민 등의 화합물과 결합체를 형성할 수 있는 능력을 가지고 있습니다 [36]. 이 과정에서, 페놀 성질의 글리코시드, 메틸화, 메톡시화, 아실화 화합물이 합성됩니다. 이전 연구에서 밝혀진 바와 같이, 플라보노이드는 3, 5, 7, 2, 3', 4', 5' 위치에서 수산화 반응을 겪습니다(그림 3). 또한, 포도당, 람노오스, 갈락토오스, 아라비노오스를 포함하는 3번 또는 7번 위치에서 글리코시드 결합이 형성됩니다[37]. 일부 연구자들은 폴리페놀 배당체의 형성 과정에서 β-글리코시드 결합이 하나 이상의 당 잔기(단당류, 이당류, 올리고당)를 수산기(O-글리코시드) 또는 방향족 고리의 탄소 원자(C-글리코시드)에 연결한다고 보고합니다[38].

문헌에 따르면 [25], PC는 두 가지 주요 특성으로 특징지어집니다: 항산화 특성과 산화에 대한 민감도를 결정하는 활성 감소, 그리고 금속 킬레이트화 활동과 효소, 수송 단백질, 수용체 등의 단백질에 대한 친화성에 기인하는 결합 특성. 식물과 동물 세포에서 이러한 2차 대사 산물의 생물학적 활성을 결정하는 것은 바로 이러한 특성입니다.

PC의 생물학적 활성은 항산화 특성을 통해 자주 평가됩니다 [4,39]. 이러한 특성은 방향족 고리, 이중 결합, 수많은 작용기를 포함하는 구조적 구성에서 비롯됩니다 [8,37]. PC는 세포에 존재하는 활성 산소 종(ROS)과 상호 작용하며, 이 활성 산소 종은 고농도일 때 세포 내 산화 스트레스를 유발합니다(그림 7).

Figure 7. Polyphenols prevent the development of oxidative stress in plant cells induced by various reactive oxygen species.

PCs scavenge hydroxyl radicals (OH) and superoxide anion radicals (O2) while also neutralizing active oxygen species such as hydrogen peroxide (H2O2) or singlet oxygen (1O2) [17]. As a result, they can prevent radical reactions instigated by these ROS, including lipid peroxidation, protein oxidation, oxidative damage to nucleic acids, alterations in the cytoskeleton, and other processes [18,40]. The antioxidant capacity of PCs is mainly determined by the number of hydroxyl groups in the molecule [7] as well as by the methylation and esterification of the compounds [35].

Some differences in the interactions between various plant PCs and ROS should be underlined. For instance, catechin gallates exhibit high activity against superoxide radicals exclusively (O2), while luteolin and kaempferol demonstrate activity against hydroxyl radicals (OH) [41]. The antioxidant activity of catechins is attributed to the ability of the hydroxyl groups of the catechol moiety to forge hydrogen bonds with the two oxygen atoms of lipid peroxide radicals [42]. The antioxidant activity of flavonoids (derivatives of luteolin and apigenin) isolated from celery leaves hinges on the location and quantity of -OH groups on the B-ring in their structures, as elucidated in a study by Wen et al. [43] based on data concerning DPPH• scavenging capacity and ABTS+• scavenging capacity. For some flavonoids, in particular quercetin and its glycosides, a higher activity of aglycones was noted [44,45].

The antioxidant activity of PCs in plants can also be attributed to their ability to chelate microelements; to inhibit enzymes involved in ROS formation, such as glutathione-S-transferase, microsomal monooxygenase, mitochondrial succinoxidase, NADPH oxidase, and xanthine oxidase; and to enhance the activity of high-molecular-weight antioxidants (enzymes) capable of scavenging radicals [26]. These mechanisms can operate independently or in specific combinations, which hinders their study [8,18].

While the formation of PCs is a characteristic feature across all members of the plant kingdom, their content and composition can vary significantly among different plant species and even within their respective organs [8,15,46]. In most instances, their accumulation remains below 1% of the dry weight [47,48,49]. However, there are exceptions, such as Camellia sinensis, where the PC content can surpass 20% of the dry weight [50]. It is noteworthy that the content of PCs tends to be higher, and their composition more diverse, in the above-ground parts of plants compared to their underground counterparts [51,52].

As previously mentioned, plants produce a wide variety of PCs with extremely diverse structural characteristics [8]. While flavonols are almost always present in chlorophyll-containing plant cells, they are rare in the absence of these organelles. In contrast, phenylpropanoids tend to exhibit relatively higher levels in such scenarios [8,46]. Based on these findings, we assume that the biosynthesis of PCs in plants is significantly influenced by the level of their intracellular differentiation and the functionality of chloroplasts, which are among the primary sites of their synthesis [15,53,54].

그림 7. 폴리페놀은 다양한 활성 산소에 의해 유발되는 식물 세포의 산화 스트레스 발생을 방지합니다.

폴리페놀은 수산기(OH)와 슈퍼옥사이드 음이온(O2)을 제거하는 동시에 과산화수소(H2O2)나 일중항 산소(1O2)와 같은 활성 산소를 중화합니다 [17]. 그 결과, 지질 과산화, 단백질 산화, 핵산의 산화적 손상, 세포 골격의 변화, 그리고 기타 과정 등 이러한 ROS에 의해 유발되는 급진적인 반응을 방지할 수 있습니다 [18,40]. PC의 항산화 능력은 주로 분자 내 수산기 수 [7]와 화합물의 메틸화 및 에스테르화에 의해 결정됩니다 [35].

다양한 식물 PC와 ROS 간의 상호 작용에 약간의 차이가 있다는 점을 강조해야 합니다. 예를 들어, 카테킨 갈레이트는 과산화수소 라디칼(O2)에 대해서만 높은 활성을 나타내는 반면, 루테올린과 캄페롤은 수산기 라디칼(OH)에 대한 활성을 나타냅니다 [41]. 카테킨의 항산화 활성은 카테콜 모이어티의 수산기가 지질 과산화물 라디칼의 두 산소 원자와 수소 결합을 형성하는 능력에 기인합니다 [42]. 셀러리 잎에서 분리된 플라보노이드(루테올린과 아피제닌의 유도체)의 항산화 작용은 DPPH• 소거 능력과 ABTS+• 소거 능력에 관한 Wen 등의 연구에서 밝혀진 바와 같이, 구조상 B-링에 있는 -OH 그룹의 위치와 양에 달려 있습니다. [43] 일부 플라보노이드, 특히 케르세틴과 그 배당체의 경우, 아글리콘의 활성이 더 높게 나타났습니다 [44,45].

식물에서 PC의 항산화 작용은 미량 원소를 킬레이트하는 능력, 글루타티온-S-트랜스퍼라제, 미소체 모노옥시게나제, 미토콘드리아 숙시노키나제, NADPH 옥시다제, 크산틴 옥시다제와 같은 ROS 형성에 관여하는 효소를 억제하는 능력, 그리고 라디칼을 제거할 수 있는 고분자량 항산화제(효소)의 활성을 향상시키는 능력 때문일 수 있습니다[26]. 이러한 메커니즘은 독립적으로 또는 특정 조합으로 작동할 수 있기 때문에 연구가 어렵습니다 [8,18].

PC의 형성은 식물계의 모든 구성원에게 공통된 특징이지만, 그 내용과 구성은 식물 종에 따라, 심지어는 각 기관에 따라 크게 다를 수 있습니다 [8,15,46]. 대부분의 경우, PC의 축적량은 건조 중량의 1% 미만으로 유지됩니다 [47,48,49]. 그러나, 동백나무(Camellia sinensis)와 같은 예외가 있는데, 이 식물의 경우 건조 중량의 20%를 초과하는 PC 함량을 보입니다 [50]. 지상부의 식물에서는 지하부에 비해 PC의 함량이 더 높고, 그 구성도 더 다양하다는 점은 주목할 만합니다 [51,52].

앞서 언급한 바와 같이, 식물은 매우 다양한 구조적 특성을 가진 다양한 종류의 PC를 생산합니다 [8]. 플라보놀은 엽록소를 함유한 식물 세포에 거의 항상 존재하지만, 이러한 세포 기관이 없는 경우에는 드뭅니다. 반면에, 페닐프로파노이드는 이러한 상황에서 상대적으로 높은 수준을 보이는 경향이 있습니다 [8,46]. 이러한 연구 결과에 근거하여, 우리는 식물의 PC 생합성이 세포 내 분화 수준과 PC 합성의 주요 장소인 엽록체의 기능에 의해 상당한 영향을 받는다고 가정합니다 [15,53,54].

3. Biosynthesis of Polyphenols

The biosynthesis of PCs is a crucial component of plant secondary metabolism. The synthesis of their diverse structural forms occurs through two main metabolic pathways: the shikimate and aceto-malonate pathways [8,9,10].

The name of the shikimate pathway originates from shikimic acid, which is the primary precursor in the biosynthesis of aromatic amino acids (L-phenylalanine, L-tyrosine, and L-tryptophan) as well as PCs [55,56]. Their substrates are products of primary metabolism: phosphoenolpyruvate from glycolysis and erythrose-4-phosphate from the pentose phosphate pathway (Figure 8). The 3-deoxy-D-arabinohexulose-7-phosphate, formed through their condensation, subsequently undergoes transformation into shikimic acid through a series of intermediate compounds catalyzed by enzyme-driven processes. As a result of additional transformations, shikimic acid can give rise to various hydroxybenzoic acids, such as p-hydroxybenzoic acid, protocatechuic acid, and gallic acid [10].

3. 폴리페놀의 생합성

폴리페놀의 생합성은 식물 2차 대사의 중요한 구성 요소입니다. 폴리페놀의 다양한 구조적 형태는 두 가지 주요 대사 경로를 통해 합성됩니다: 시키메이트 경로와 아세토-말론산 경로 [8,9,10].

시키메이트 경로의 이름은 방향족 아미노산(L-페닐알라닌, L-티로신, L-트립토판)과 PC의 생합성에서 주요 전구물질인 시킴산에서 유래되었습니다 [55,56]. 이들의 기질은 1차 대사 산물입니다: 해당 과정의 포스포에놀피루브산과 5탄당 인산 경로의 에리트로스-4-인산(그림 8). 그들의 축합을 통해 형성된 3-deoxy-D-arabinohexulose-7-phosphate는 효소 작용에 의해 촉매 작용을 받는 일련의 중간 화합물을 통해 시킴산으로 변형됩니다. 추가적인 변형의 결과로, 시킴산은 p-하이드록시벤조산, 프로토카테츄산, 갈산과 같은 다양한 하이드록시벤조산을 생성할 수 있습니다 [10].

Figure 8. Biosynthesis pathway of phenolic compounds.

The predominant purpose of shikimic acid is to serve as a precursor for the synthesis of aromatic amino acids such as L-phenylalanine and L-tyrosine [9,10]. In this process, the deamination of L-phenylalanine by the key phenolic metabolism enzyme phenylalanine ammonia-lyase (PAL) results in the formation of trans-cinnamic acid [57]. This stage corresponds to the beginning of the phenylpropanoid pathway of PC biosynthesis. Trans-cinamic acid is regarded as one of the earliest phenolic metabolites produced in plant cells, acting as a bridge between the metabolism of aromatic amino acids and PCs [58,59]. The involvement of tyrosine ammonia-lyase in the transformation of L-tyrosine to trans-cinnamic acid has also been reported. However, its deamination is generally less pronounced compared to L-phenylalanine, which is the primary precursor for phenolic compounds [57]. It is suggested that in monocots, PAL can also function as L-tyrosine ammonia-lyase, acting as a bifunctional enzyme for both L-phenylalanine and L-tyrosine and converting L-tyrosine to p-coumaric acid (without the 4-hydroxylation step), albeit with reduced efficiency [58].

그림 8. 페놀 화합물의 생합성 경로.

시킴산의 주된 목적은 L-페닐알라닌과 L-티로신 같은 방향족 아미노산의 합성을 위한 전구체로 작용하는 것입니다 [9,10]. 이 과정에서, 주요 페놀 대사 효소인 페닐알라닌 암모니아 분해효소(PAL)에 의한 L-페닐알라닌의 탈아미노화는 트랜스-신남산의 형성을 초래합니다 [57]. 이 단계는 PC 생합성의 페닐프로파노이드 경로의 시작에 해당합니다. 트랜스-신남산은 식물 세포에서 생성되는 가장 초기의 페놀 대사 산물 중 하나로 간주되며, 방향족 아미노산과 PC의 대사 사이에서 다리 역할을 합니다 [58,59]. L-티로신이 트랜스-신남산으로 변형되는 과정에서 티로신 암모니아 분해효소의 관여가 보고된 바 있습니다. 그러나, 그 탈아미노화는 페놀 화합물의 주요 전구체인 L-페닐알라닌에 비해 일반적으로 덜 뚜렷합니다 [57]. 단자엽 식물에서 PAL은 L-페닐알라닌과 L-티로신을 위한 이중 기능성 효소로서 작용하고, L-티로신을 p-쿠마르산으로 전환하는(4-하이드록실화 단계 없이) L-티로신 암모니아-리아제로서의 기능도 할 수 있지만, 효율성은 떨어지는 것으로 알려져 있습니다[58].

Enzymes: DAHPS, 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase; PAL, phenylalanine ammonia-lyase; C4H, cinnamate 4-hydroxylase; 4CL,4-coumaroyl-CoA ligase; CHS, chalcone synthase; CHI, chalcone isomerase; F3H, flavanone 3-hydroxylase; FLS, flavonol synthase; FNS, flavone synthase; IFS, isoflavon synthase; DFR, dihydroflavonol 4-reductase; LAR, leucoanthocyanidin reductase; ANS, anthocyanidin synthase; ANR, anthocyanidin reductase.

A series of subsequent hydroxylations of trans-cinnamic acid leads to the formation of other hydroxycinnamic acids. Typically, these compounds do not accumulate in their free form within plant tissues, as they undergo further transformations. Among the most significant of them are β-oxidation resulting in hydroxybenzoic acids, reduction leading to cinnamic alcohols involved in lignin biosynthesis, the creation of various acyl derivatives and complex esters (such as chlorogenic acid), and the synthesis of coumarins [30,31,60]. This completes the formation of the major components in the phenylpropanoid pathway, which is a central component in the biosynthesis of natural PCs [61,62].

The aceto-malonate pathway plays a significant role in the biosynthesis of phenolic compounds [9,63]. In higher plants, this pathway is usually coupled with the phenylpropanoid pathway and leads to the formation of flavonoids [64]. Ring B in their structures is formed through the shikimate pathway (from hydroxycinnamic acid), while ring A is formed through the aceto-malonate pathway [63]. p-Coumaroyl-CoA and three molecules of malonyl-CoA are used as starting compounds (substrates), and their condensation leads to the formation of chalcone [65]. This reaction is catalyzed by chalcone synthase (CHS), the key enzyme in the biosynthesis of flavonoids [63,66]. The formed chalcone naringenin can easily be transformed into flavanone naringenin through the action of chalcone-flavanone isomerase (CHI). After undergoing changes in the oxidation state of the central heterocyclic ring of the molecule (due to redox reactions), naringenin can serve as a precursor for all other classes of flavonoids (flavan-3-ols, flavanones, flavones, anthocyanins, etc.) except for chalcones and dihydrochalcones. Enzymes involved in the formation of various classes of flavonoids have been extensively described in the literature [8,9,64,67].

Typically, most monomeric forms of phenolic compounds are not end products of phenolic metabolism; instead, they can participate in the formation of more complex oligomeric and polymeric structures. Among these are proanthocyanidins, which are derivatives of flavan-3-ols and are distributed in higher plant tissues [68]. Their biosynthesis occurs in the final stages of the flavonoid pathway, and the process of condensing flavan-3-ols into proanthocyanidins still remains unclear [69]. It is postulated that condensation can occur either through enzymatic pathways involving peroxidase, polyphenol oxidase, and laccase or through non-enzymatic means, specifically sequential autocondensation of flavan-3-ols [64,65,68].

In addition to biochemical studies on the biosynthesis of PCs, which remain relevant, the current emphasis is focused on studying the genes responsible for phenolic metabolism and their regulatory mechanisms. This shift is facilitated by advancements in molecular biology and functional genomics [13,59,70]. The field of genetic engineering is actively progressing to optimize plant phenolic profiles, with the primary aim of expediting the production of pharmacologically valuable compounds among other objectives [63,70,71].

More emphasis is currently being placed on studying gene expression‎ related to the biosynthesis of PCs. For instance, gene networks responsible for regulating biochemical processes in Camellia sinensis have been documented [72,73]. Transcriptomic research has revealed metabolic pathways and crucial genes implicated in the biosynthesis, transport, and metabolism of catechins, caffeine, and L-theanine [74,75].

Gene expression‎ responsible for metabolite biosynthesis is under the control of various processes, including transcription, post-translational modifications, and micro-regulators like non-coding RNAs [58]. Among the key regulators of PC biosynthesis, transcription factors (TFs) stand out. TFs are DNA-binding proteins that bind to the promoter regions of target genes, modifying the rate of transcription initiation. In response to environmental signals (both internal and external, including phytohormones and abiotic factors), TFs can affect both structural and regulatory enzyme genes, thus influencing the accumulation of secondary metabolites (Figure 9).

트랜스-신남산의 연속적인 일련의 수산화 작용은 다른 하이드록시신남산의 형성을 유도합니다. 일반적으로, 이러한 화합물은 식물 조직 내에서 자유 형태로 축적되지 않고, 추가적인 변형을 거칩니다. 그 중에서도 가장 중요한 것은 β-산화로 인한 하이드록시벤조산, 리그닌 생합성에 관여하는 신남 알코올로 이어지는 환원, 다양한 아실 유도체와 복합 에스테르(클로로겐산 등)의 생성, 쿠마린의 합성입니다 [30,31,60]. 이것으로 페닐프로파노이드 경로의 주요 구성요소 형성이 완료됩니다. 이 경로는 천연 PC의 생합성에서 중심적인 역할을 합니다 [61,62].

아세토-말론산 경로는 페놀 화합물의 생합성에서 중요한 역할을 합니다 [9,63]. 고등 식물에서 이 경로는 보통 페닐프로파노이드 경로와 결합되어 플라보노이드의 형성을 유도합니다 [64]. 그들의 구조에서 B 고리는 시키메이트 경로(하이드록시신남산으로부터)를 통해 형성되는 반면, A 고리는 아세토-말론산 경로를 통해 형성됩니다 [63]. p-쿠마로일-CoA와 3개의 말론일-CoA 분자가 출발 화합물(기질)로 사용되며, 이들의 축합은 칼콘의 형성을 유도합니다 [65]. 이 반응은 플라보노이드 생합성의 핵심 효소인 칼콘 신타제(CHS)에 의해 촉매됩니다 [63,66]. 이렇게 형성된 칼콘 나링게닌은 칼콘-플라바논 이소머라제(CHI)의 작용을 통해 쉽게 플라바논 나링게닌으로 변형될 수 있습니다. 산화 환원 반응으로 인해 분자의 중심 헤테로사이클릭 고리의 산화 상태가 변화한 후, 나링게닌은 칼콘과 디하이드로칼콘을 제외한 모든 다른 종류의 플라보노이드(플라반-3-올, 플라바논, 플라본, 안토시아닌 등)의 전구물질로 작용할 수 있습니다. 다양한 종류의 플라보노이드 형성에 관여하는 효소는 문헌에 광범위하게 기술되어 있습니다 [8,9,64,67].

일반적으로, 대부분의 단량체 형태의 페놀 화합물은 페놀 대사의 최종 산물이 아닙니다; 대신, 이들은 더 복잡한 올리고머 및 고분자 구조의 형성에 관여할 수 있습니다. 그 중에는 플라반-3-올의 유도체인 프로안토시아니딘이 있으며, 이들은 고등 식물 조직에 분포되어 있습니다 [68]. 그들의 생합성은 플라보노이드 경로의 마지막 단계에서 일어나며, 플라반-3-올을 프로안토시아니딘으로 응축하는 과정은 아직 명확하지 않습니다 [69]. 응축은 퍼옥시다아제, 폴리페놀 옥시다아제, 락케이스를 포함하는 효소 경로 또는 플라반-3-올의 순차적 자가응축과 같은 비효소적 수단을 통해 일어날 수 있다고 가정합니다 [64,65,68].

PC의 생합성에 대한 생화학 연구가 여전히 관련성이 있지만, 현재는 페놀 대사에 관여하는 유전자와 그 조절 메커니즘을 연구하는 데 중점을 두고 있습니다. 이러한 변화는 분자 생물학과 기능 유전체학의 발전에 의해 촉진되었습니다 [13,59,70]. 유전공학 분야는 식물 페놀 프로파일을 최적화하기 위해 활발히 발전하고 있으며, 그 주요 목표는 다른 목표들 중에서도 약리학적으로 가치 있는 화합물의 생산을 촉진하는 것입니다 [63,70,71].

현재는 PC의 생합성과 관련된 유전자 발현을 연구하는 데 더 많은 중점을 두고 있습니다. 예를 들어, Camellia sinensis의 생화학 과정을 조절하는 유전자 네트워크가 문서화되었습니다 [72,73]. 전사체 연구에 따르면, 카테킨, 카페인, L-테아닌의 생합성, 수송, 대사에 관여하는 대사 경로와 핵심 유전자가 밝혀졌습니다 [74,75].

대사 산물 생합성을 담당하는 유전자 발현은 전사, 번역 후 변형, 비코딩 RNA와 같은 마이크로 조절 인자를 포함한 다양한 과정의 통제하에 있습니다 [58]. PC 생합성의 주요 조절 인자 중에는 전사 인자(transcription factors, TF)가 두드러집니다. TF는 표적 유전자의 프로모터 영역에 결합하여 전사 개시 속도를 조절하는 DNA 결합 단백질입니다. TF는 환경 신호(식물 호르몬과 비생물적 요인을 포함한 내부 및 외부 환경 모두)에 반응하여 구조적 효소 유전자와 조절 효소 유전자 모두에 영향을 미칠 수 있으며, 이로 인해 2차 대사 산물의 축적에 영향을 미칩니다(그림 9).

Figure 9. The effect of the abiotic factors on the activity of genes and transcriptional factors, regulating the polyphenol accumulation in plants.

Numerous families of TFs are known to be involved in phenolic metabolism, with one of the most prominent being the MYB TF family. They play a significant role in plant defense against various stresses [59,64]. It has been demonstrated that numerous MYBs play a regulatory role in the phenylpropanoid and flavonoid pathways within plants. Some of these TFs function as activators of enzyme genes, while others act as repressors [60]. For instance, the overexpression‎ of the TF MusaMYB31 in bananas (Musa cultivar Rasthal) led to a reduction in the transcript levels of most genes within the phenylpropanoid and flavonoid pathways [76]. In contrast, studies conducted on poplar trees (Populus spp.) revealed that the TF PtMYB115 binds to the promoter regions of ANR1 and LAR3 genes, enhancing the expression‎ of these genes and subsequently resulting in an increased accumulation of proanthocyanidins [77]. Furthermore, in grapevine (Vitis vinifera), the VvMYB5a transcription factor contributes to flavonoid synthesis by inhibiting lignin production. This unique regulatory mechanism helps maintain a balance in carbon flow between lignin and flavonoids in the plant [60]. Notably, a single MYB transcription factor can exert control over multiple genes within a pathway, and, conversely, a single gene can be subject to regulation by several MYB proteins [78].

Often, TFs are presented in the form of complexes. The MBW complex, composed of MYB, bHLH, and WD40 proteins, is a central transcriptional regulator in flavonoid biosynthesis [78]. This complex activates structural genes responsible for the flavonoid biosynthesis process, particularly anthocyanins. In several plants such as Helianthus annuus L., Arabidopsis thaliana, Camellia sinensis, Narcissus tazetta, Medicago truncatula, Vitis vinifera, and others, these transcription factors have been well characterized functionally [79].

Understanding the mechanisms of gene regulation in phenolic metabolism holds the potential to enhance the production of pharmacologically valuable secondary plant metabolites.

페놀 대사에 관여하는 TF의 가족은 여러 가지가 알려져 있는데, 그 중에서도 MYB TF 가족이 가장 두드러집니다. 이 가족은 다양한 스트레스에 대한 식물 방어에 중요한 역할을 합니다 [59,64]. 수많은 MYB가 식물 내 페닐프로파노이드와 플라보노이드 경로의 조절 역할을 한다는 사실이 입증되었습니다. 이들 TF 중 일부는 효소 유전자의 활성화제로서 기능하는 반면, 다른 일부는 억제제로서 기능합니다 [60]. 예를 들어, 바나나(Musa cultivar Rasthal)에서 TF MusaMYB31의 과발현은 페닐프로파노이드 및 플라보노이드 경로 내의 대부분의 유전자의 전사체 수준을 감소시켰다 [76]. 반면에 포플러 나무(Populus spp.)에 대한 연구에 따르면, TF PtMYB115는 ANR1과 LAR3 유전자의 프로모터 영역에 결합하여 이들 유전자의 발현을 촉진하고, 결과적으로 프로안토시아니딘의 축적을 증가시킵니다 [77]. 또한, 포도나무(Vitis vinifera)에서 VvMYB5a 전사 인자는 리그닌 생성을 억제함으로써 플라보노이드 합성에 기여합니다. 이 독특한 조절 메커니즘은 식물에서 리그닌과 플라보노이드 사이의 탄소 흐름의 균형을 유지하는 데 도움이 됩니다 [60]. 특히, 하나의 MYB 전사 인자는 하나의 경로 내에서 여러 유전자를 제어할 수 있으며, 반대로 하나의 유전자는 여러 MYB 단백질에 의해 조절될 수 있습니다 [78].

종종 TF는 복합체의 형태로 제시됩니다. MYB, bHLH, WD40 단백질로 구성된 MBW 복합체는 플라보노이드 생합성의 중심 전사 조절 인자입니다 [78]. 이 복합체는 플라보노이드 생합성 과정, 특히 안토시아닌 생합성을 담당하는 구조 유전자를 활성화합니다. Helianthus annuus L., Arabidopsis thaliana, Camellia sinensis, Narcissus tazetta, Medicago truncatula, Vitis vinifera 등 여러 식물에서 이러한 전사 인자는 기능적으로 잘 특성화되어 있습니다 [79].

페놀 대사에서의 유전자 조절 메커니즘을 이해하면 약리학적으로 가치 있는 2차 식물 대사 산물의 생산을 향상시킬 수 있는 잠재력이 있습니다.

4. Abiotic Factors and Polyphenol Accumulation in Plants

The interaction between plants leading a sessile lifestyle and their surrounding environment constitutes an indispensable prerequisite for their growth and development. However, fluctuating environmental conditions can exert stressful effects on them (Figure 10).

Figure 10. Environmental factors that can have a stressful effect on plants.

In these instances, the plant survival and preservation of their productivity and quantitative and qualitative characteristics, which are particularly important for agricultural and medicinal plants, depend on their adaptive potential [15,17,61]. The exploration of processes related to adaptation and resilience is one of the up-to-date domains within physiology, biochemistry, and molecular biology. These studies provide insights into the mechanisms of adaptation and facilitate the development of strategies to enhance plant resistance against exogenous influences. Notably, these strategies have proven effective in the selective breeding and development of transgenic stress-tolerant plants [71,79].

It is established that exposure to stressors leads to an excessive accumulation of reactive oxygen species (ROS) within plant cells. These ROS molecules interact with various biomolecules, including lipids, proteins, DNA, RNA, and other metabolites, exerting toxic effects that can ultimately result in cell death [80]. And in this case, an important role is assigned to antioxidants, including low-molecular-weight PCs. Their accumulation typically rises during exposure to stressful conditions, and this phenomenon is considered a benchmark for their resistance [2,40,81]. In the following sections, we will discuss these issues.

4.1. Light

Light is one of the “key” factors profoundly influencing plant life (Figure 11). This factor impacts many metabolic processes, including the biosynthesis of PCs [59]. Its regulatory role extends to numerous enzymes involved in phenolic metabolism, with their activation accompanied by the accumulation of these metabolites, primarily in their monomeric forms [9,15]. Additionally, light exposure contributes to the formation of chloroplasts, which represent one of the main sites for the biosynthesis of these secondary metabolites [53,54]. At the same time, light can also act as a stress-inducing factor, leading to an increase in the ROS levels in cells and even triggering an event termed an ‘oxidative burst’ [5].

Figure 11. Light and its effect on plants.

The enhancement of the accumulation of phenolic antioxidants in plant tissues under light exposure has been discussed in several review articles [6,15]. The stimulatory effect of light on the levels of flavonoids, proanthocyanidins, and some other metabolites has been documented not only in leaves but also in in vitro cultures of Camellia sinensis [82,83]. Moreover, a discernible correlation has been established between the accumulation of proanthocyanidins and the expression‎ of phenolic metabolism genes, encompassing PAL, flavanone 3-hydroxylase (F3H), flavonoid 3′-hydroxylase (F3′H), dihydroflavonol reductase (DFR), and anthocyanidin reductase1 (ANR1), predominantly observed within leaf tissues. Furthermore, a correlation between proanthocyanidin accumulation and the expression‎ of phenolic metabolism genes, such as PAL, flavanone 3-hydroxylase (F3H), flavonoid 3′-hydroxylase (F3′H), dihydroflavonol reductase (DFR), and anthocyanidin reductase1 (ANR1), was observed in leaves. On the other hand, the formation of O-glycosylated flavonols correlated with the expression‎ of chalcone synthase (CHS) and flavonoid 3′,5′-hydroxylase (F3′5′H).

Considerable emphasis is put on the investigation of how the spectral composition of light (red, far-red, blue, and green) influences the biosynthesis of PCs and their accumulation within plant tissues [5,6,15,59]. The stimulating impact of blue light on the production of these metabolites has been documented across a diverse array of plant species, including Brassica napus, B. campestris L. ssp. chinensis var. communis, and B. oleracea var. alboglabra Bailey [84,85]. Within callus cultures of Camellia japonica, the highest accumulation of PCs, encompassing flavonoids, was observed under the combined influence of red and blue light or, alternatively, blue and green light [86]. The involvement of MYB transcription factors in the light regulation of PC biosynthesis has also been reported [11]. In tartary buckwheat plants (Fagopyrum tataricum), a novel transcription factor has been identified and characterized, SG7 R2R3-MYB—FtMYB6, the promoter of which becomes induced by light [87]. Based on the acquired data, FtMYB6 stimulated the activity of FtF3H and FtFLS1 promoters while suppressing that of the Ft4CL promoter, thereby fostering the biosynthesis of flavonols within plant cells.

Overall, these divergences in the plant’s responsive reactions to light and/or its spectral composition are rooted in the functionalities of specific photoreceptors, attuned to distinct regions of the light spectrum [15,59]. Different classes of photoreceptors perceive wavelengths corresponding to blue (B, 445–500 nm), green (G, 500–580 nm), red (R, 620–700 nm), and far-red (FR, 700–775 nm) light. Their functional activity is regulated by the intensity and duration of the light exposure [88]. It implies that there is potential for regulating photomorphogenetic and biochemical processes, encompassing the accumulation of phenolic bioantioxidants, through artificial lighting as an economically valuable approach in industrial plant cultivation.

The presence of a significant number of studies on the effect of light on the accumulation of PCs in plants, their biosynthesis, and their gene regulation (some of them are presented in this review) does not yet allow us to obtain an accurate answer about the mechanism of its action. So far, we only have information about the response of different plants (species and varieties), which, in some cases, differs significantly. These differences are due to their physiological state, growing conditions, intensity and duration of light exposure, and other environmental factors. Consequently, biochemical and molecular genetic aspects of PC biosynthesis in plants exposed to light can be considered one of the promising and important areas of plant biology.

4.2. UV Radiation

One of the prominent challenges of our time is the shifting climate conditions across the planet. Within this context, particular attention is drawn to the effects of increased doses of solar radiation, including its ultraviolet (UV) range [89]. The intensity of this radiation is contingent upon the quantity and composition of anthropogenic emissions of greenhouse gases (carbon dioxide, methane, and nitrous oxide), cloud formation dynamics, and the extent of sea ice and snow cover on the Earth’s surface.

UV light is categorized into distinct ranges: UV-A (315–400 nm), UV-B (280–315 nm), and UV-C (200–280 nm). Notably, UV-C does not reach the Earth’s surface, whereas UV-A fully penetrates the ozone layer (Figure 12). UV-B, accounting for 5% of the total UV radiation, is considered one of the most potent stressors for the vitality of numerous organisms [61,90].

Figure 12. Ranges of UV light and its penetration through the ozone layer of the atmosphere.

Elevated levels of UV-B radiation are commonly observed in high-altitude regions and in areas with ‘ozone holes’ that form due to a reduction in stratospheric ozone concentration [91,92]. Exposure to this factor results in alterations in the morphophysiological, biochemical, and genetic characteristics of plants, the manifestation of which is contingent upon the ‘dosage’ of this stress factor [59,93]. Frequently, notable instances of their growth retardation, decreased productivity, reduced photosynthetic pigment content and intensity, the activation of mutagenic processes, and the disruption of DNA structure were observed [7,94]. In addition, the ‘ultimate’ biological effect of UV-B radiation exhibits not only a rapid response but also a temporally distant ‘outcome,’ attributed to the transformation of the de novo biosynthesis of various cellular components [95].

Despite all of these alterations, plants, as a whole, exhibit greater resilience to UV-B radiation compared to microorganisms and animals. This phenomenon could be attributed to the formation and functioning of adaptive mechanisms, including the accumulation of “protective” substances [61,94]. Among them are natural phenolic antioxidants, which, in this context, not only deactivate reactive oxygen species but also absorb the short-wavelength portion of solar radiation. As a result, they provide both physical and metabolic protection to cells against the damaging effects of UV-B radiation [89,90].

In most cases, exposure to UV-B rays increases the content of various phenolic metabolites within plant cells. One particularly striking illustration of this phenomenon was observed in a cell culture of rose (Rosa damascena) grown in in vitro conditions, where the accumulation of flavonoids increased by nearly 15 times [96]. Following exposure to UV-B radiation, the levels of flavonoids within olive leaves, such as 4′-methoxylutelin and 4′- or 3′-methoxylutelinglucoside, experienced an increase. Moreover, the phenylpropanoid β-hydroxy-verbascoside (a derivative of hydroxycinnamic acid) emerged [97]. Against the backdrop of changes in PC accumulation, the activation of phenolic metabolism genes occurred. For instance, in Mangifera indica, 3 out of the 21 chalcone synthase genes (MiCHS4, MiCHS1, and MiCHS17) were triggered in response to UV-B radiation exposure [98].

In conclusion, it is crucial to emphasize that the effects of increased UV-B radiation doses are contingent upon the endogenous content of PCs in plants, their composition, and their compartmentalization within plant tissues. This has been elucidated in a range of reviews [92,97,99].

4.3. Temperature

The growth and development of plants occur across a diverse temperature range [9,61]. However, significant fluctuations in temperature can impose stress, affecting physiological and biochemical processes, thereby leading to growth inhibition and developmental disturbances [100]. In this case, PCs play a crucial role in protecting plants from unfavorable temperature conditions.

It is well established that exposure to cold stress frequently triggers a heightened accumulation of anthocyanins in plants [101]. At the same time, an increase in the expression‎ of genes responsible for flavonoid biosynthesis has also been noted. Particularly, in the case of Brassica rapa, a close correlation has been established between the plant resilience to cold stress and the expression‎ of genes encoding dihydroflavonol-4-reductase (BrDFR) and anthocyanidin synthase (BrANS) [16,102]. Furthermore, it has been reported that exposure to lowered temperatures in Malus sieversii leads to an enhanced accumulation of anthocyanins, a phenomenon attributed to the involvement in this regulatory process of the transcription factor MdMYBPA1 [65]. The accumulation of anthocyanin in purple Chinese cabbages under low-temperature conditions was mediated through the induction of the regulatory genes BrTT8 and BrMYB2. These, in turn, triggered the activation of almost all of the late-stage biosynthesis genes responsible for these phenolic metabolites (BrDFR1, BrANS1, BrUGT79B1, DrUGT75C1, and Br5MAT) [103].

Lignin, a phenolic polymer, stands as one of the most preval‎ent forms of polyphenols in plant organisms [104]. The accumulation of lignin is a typical trait in most plant cells and, to a certain extent, contributes to their resilience to low temperatures. It has been reported that under cold stress conditions, its content within the epidermal cell layer increased [31]. This process facilitated the subsequent lignification of the cell wall, which “protected” intracellular contents from freezing and reduced cell damage during dehydration induced by freezing. Furthermore, there is evidence of the significant involvement of the transcription factors C2H2Zn and MYB in the biosynthesis of lignin during periods of abiotic stress exposure [105].

Changes in temperature during the vegetative phase of plants are frequently manifested by an increase, thereby affecting the plants’ antioxidant system and accumulation of PCs [17]. Through the example of Solanum lycopersicon, it was demonstrated that flavonols reduce the accumulation of reactive oxygen species induced by high-temperature stress [106]. Under elevated temperatures, an increase in the content of flavonoids and phenylpropanoids in Glycine max was observed [107]. It should also be noted that the activation of these processes may vary throughout the day and night. Through the example of grapevine (Vitis vinifera), it has been demonstrated that in darkness, with the temperature maintained at 35 °C, no changes in the quantity of flavonols were observed. However, at a more extreme temperature (45 °C), it decreased both during the night and daytime [108].

Molecular and genetic studies on chrysanthemum (Chrysanthemum cultivar ‘Fencui’) revealed a novel atypical transcription factor of subgroup 7 (SG7) R2R3-MYB (CmMYB012). This factor was induced in response to prolonged high-temperature exposure and inhibited flavonoid biosynthesis [109]. Moreover, it was demonstrated that it exerts an inhibitory effect on anthocyanin biosynthesis by suppressing the expression‎ of CmCHS, CmDFR, CmANS, and CmUFGT.

An analysis of the literature reveals diversity in plant responses to temperature stimuli in terms of PCs: low temperatures generally lead to the activation of their biosynthesis, particularly anthocyanins, whereas high temperatures suppress this process [103,109].

All of this indicates that changes in the temperature of the surrounding environment influence the biosynthesis of various classes of PCs in plant tissues, and this process is dependent on the functional activity of genes responsible for their synthesis.

4.4. Heavy Metals

Among the abiotic stressors are heavy metals, a result of human technological activities, which mostly exert a negative impact on plant growth and metabolism [110]. The toxicity threshold of heavy metals hinges on the chemical characteristics of individual representatives, the form of their presence in the soil solution or other substrates, and the concentration and duration of exposure [111,112]. Certain heavy metals, including zinc, copper, and molybdenum, at elevated concentrations exhibit toxicity to plants, whereas at low levels, they play a vital role in supporting essential physiological processes. Heavy metals not involved in metabolic processes, like cadmium, lead, and mercury, can be toxic even at low levels [113].

Exposure to heavy metals is responsible for interrupting homeostasis in plants, which is mediated by increasing ROS levels in their cells [110]. But, in spite of that, plants keep surviving due to the functionality of antioxidant systems, where key positions belong to direct-acting antioxidants [13,114]. Among them are low-molecular-weight compounds, including PCs, which, in addition to neutralizing ROS, also act as agents chelating with heavy metals, thereby inhibiting metal-catalyzed free radical oxidation reactions [18,115]. Additionally, the ability of PCs to interact with the HM arises from the high nucleophilicity of their benzene rings and depends on the number and location of hydroxyl groups [7]. Flavonoids, the predominant class of PCs, play a crucial role in the chelation process with heavy metals. It has been revealed that in Gynura pseudochina plants, many of them are capable of chelating zink and cadmium, while catechins can chelate iron [116].

In most cases, plants’ exposure to heavy metals leads to an increased accumulation of various PCs within them. This is supported by data on the accumulation of catechins and quercetin in the roots of Pínus and Zea mays plants [7,117]. Callus cultures of Amaranthus caudatus and Ginkgo biloba, when exposed to copper, exhibited an increase in the content of flavonoids [19,118].

On the other hand, there are reports of a reduction in the content of PCs in plant tissues following exposure to heavy metals. The excess nickel in the surrounding environment led to a reduction in anthocyanin levels in the sprouts of Lactuca sativa [119]. A decrease in the levels of secondary metabolites in certain plants of the Asteraceae family has been reported under the conditions of metal-induced stress [120]. The absence of PC accumulation is attributed to the damaging effects of high levels of heavy metals, hindering the antioxidant system’s functionality and limiting the organisms’ ability to biosynthesize these metabolites.

The PC content in the plant cells is attributed to the functional activity of enzymes involved in their biosynthesis. Thus, in the sprouts of the red cabbage exposed to copper, along with an increased content of PCs, phenylalanine ammonia-lyase levels were augmented, which is responsible for the initial stages of phenolic metabolism [121]. In wheat, the activity not only of phenylalanine ammonia-lyase but also of tyrosine ammonia-lyase increased under elevated concentrations of lead and copper, and this effect was more pronounced under copper-induced stress [122].

The regulation of secondary metabolite formation in plant cells is strongly influenced by changes in the transcriptional levels of genes involved in their biosynthesis, a phenomenon directed by transcription factors (TFs), including the MYB family, the largest among them [11]. Within the latter, sub-family R2R3MYBs is the most interesting, which is involved not only in the ontogenetic development processes but also in the plants’ reactions to the stress conditions. This activity is mediated by the regulation of the biosynthesis of secondary metabolites, including flavonoids and monolignols [123]. It is established that this process occurs through the MBW (MYB-bHLH-WDR) complex, both for flavonoids and anthocyanins [61]. In plants of sweet wormwood (Artemisia annua), the overexpression‎ of genes HMGR, ADS, CPYA171, and FDS enhances the formation of artemisinin against the backdrop of the toxic influence of copper and silver. Additionally, the elevated activity of genes PAL and CHS leads to an increase in concentrations of anthocyanins and flavonoids [116]. Under metal-induced stress, the transcription levels of genes encoding enzymes of the phenylpropanoid pathway (phenylalanine ammonia-lyase, chalcone synthase, shikimate dehydrogenase, and cinnamyl alcohol dehydrogenase) are linked to an increase in the content of PCs in plant tissues [61].

All of the aforementioned evidence suggests that the enhanced plants’ capability of biosynthesis, i.e., their capacity to accumulate PCs under the influence of heavy metals, is ensured by the functioning of various mechanisms critical for the survival and competitiveness of these organisms under abiotic stress conditions. Herewith, the activation of the phenylpropanoid pathway of PC biosynthesis often correlates with an increase in plant resistance and the manifestation of PCs’ functions such as antioxidant and protective functions. All of that is crucial for enhancing the quality of plant products used in the medical, pharmacological, and nutriceutical industries while developing a strategy for public health protection.

5. Phenolic Bioantioxidants in Public Health Protection

One of the actively developing approaches for preserving and maintaining human health is the development of functional nutrition, along with the increasingly broader utilization of natural remedies [51]. This can reduce the usage of synthetic pharmacological products; enhance human vitality, including resistance to stress factors; and augment longevity (Figure 13).

Figure 13. Basic plant foods for functional nutrition and maintaining human health.

Over the past few decades, significant attention worldwide has been devoted to the search for effective natural antioxidants that protect living organisms from the damaging effects of ROS [4]. Among them, PCs hold a distinctive position, demonstrating robust antioxidant capacity and potent antimicrobial, antiviral, antiatherosclerotic, and antihypertensive effects [124,125].

While the presence of ROS is an integral part of the normal functional activities of various organisms, the “uncontrolled” production of these molecules triggers oxidative stress, ultimately leading to the development of many diseases in humans [126]. In this scenario, PCs assume a vital and imperative role in protecting and preserving public health. Their aromatic nature and highly conjugated bond system with hydroxyl groups render these metabolites excellent donors of electrons or hydrogen atoms [18]. The mechanism of antioxidant action of PCs includes their reductive capacity in neutralizing ROS, as well as their ability to chelate metal ions that trigger oxidative stress. Furthermore, they can inhibit enzymes participating in ROS formation and activate antioxidant enzymes [26].

It is important to emphasize that PCs are not synthesized within the human body but rather enter it through food chains while retaining their inherent antioxidant activity [127,128]. This is precisely why pharmacologists and other experts show significant interest in studying plants as potential “sources” of phenolic phytonutrients with diverse biological activities (Table 1).

Table 1. Plant Polyphenols and Their Pharmacological Activity.

Antimicrobial, antiviral, antiatherosclerotic, capillary-strengthening, and anticancer effects are characteristic both of plant extracts and specific natural PC representatives [124,125,136]. According to preclinical and clinical research, the prolonged consumption of a diet rich in PCs (such as quercetin, resveratrol, gallic acid, and caffeic acid) reduces the incidence of cardiovascular diseases, diabetes, cancer, and atherosclerosis and also provides protection against certain types of allergies while slowing down the progression of Alzheimer’s disease [4,127]. Reports have indicated the involvement of these plant metabolites, including flavonoids, in activating the immune response of human cells to coronavirus infection (SARS-CoV-2) [137]. It is also worth mentioning that under specific conditions (alkaline pH and high metal content), polyphenolic compounds can act as pro-oxidants. This property contributes to their anticancer activity, as they can inhibit the proliferation of cancer cells [138].

Compounds of a phenolic nature are widely distributed in fruits, vegetables, grains, nuts, spices, tea, and other crops, with their quantity varying significantly. For instance, the total concentration of polyphenols in black-eyed peas can reach 1200 (mg-eq. gallic acid/g dry weight); in pomegranate leaves, 199.26 (mg-eq. gallic acid/g dry weight); and in peppermint, 70.06 (mg-eq. gallic acid/g dry weight) [48,134,135].

Including plant-based foods with high phenolic antioxidant content in the diet can help prevent oxidative stress in the body [48,139]. However, consuming PCs in the form of high-dose bioactive supplements may lead to adverse side effects in individuals [140]. This also applies to the use of dihydroquercetin, a commonly used capillary-strengthening agent, as excessive doses can result in various metabolic disruptions within the body [141].

It is worth highlighting that PCs in plants primarily accumulate in a conjugated form (as glycosides, acylglycosides, etc.) [142]. After their entry into the human body, they undergo various transformations in the digestive tract, including deglycosylation, methylation, sulfation, and glucuronidation [124,143]. An important role in the bioavailability of PCs belongs to the microbiome of the large intestine, which is involved in the cleavage of flavonoids to phenolic acids, which contributes to their reabsorption. It has been shown that the digestibility of PCs, including flavonoids, depends on individual characteristics of a person, such as gender, age, the presence of pathologies, and genetics [8,144]. The intake of plant-derived PCs into the human body, their transportation, and their pharmacological activity have been discussed in a series of reviews in recent years [31,145,146].

The effectiveness of the prevention and treatment of human diseases when eating plant foods enriched with PCs is beyond doubt. However, they are used not only fresh but also after various treatments (heating, cooling, preservation, drying, and fermentation). In this case, the composition, content, and biological activity of PCs depend on the type of process, the duration of exposure, the intensity of the regime, and the class of these secondary metabolites. All of this can increase the bioavailability of PCs for the human body due to their structural changes [147,148].

To overcome the problem of PC bioavailability, systems for their delivery using biocompatible materials such as nanoparticles, including liposomes, phytosomes, lipid and protein nanoparticles, micelles, and natural and synthetic polymers, have been developed [149]. They allow the protection of phenolic compounds from degradation; improve their solubility, cellular absorption, and stability; and maintain pharmacological activity in the human body. For example, nanocubasomas with anthocyanin-rich Cornus mas extract had a size of 22.75 nm. This contributed to their good entry into the cells. The stability of anthocyanins in this delivery system was 92%, while in the free extract, it was 75% [150].

Despite the pharmacological activity of many PCs and their effectiveness in the prevention and treatment of a number of diseases, the commercial production of these secondary metabolites is limited. This is due to the limited nature of the plant materials used to obtain them and the difficulty in isolating individual components [151]. An important limiting factor is the development of effective “delivery systems” of PCs into the human body that ensure their bioavailability [152]. We should not forget about the effect of high doses of PCs, which are not always optimal for maintaining human life. All of this requires further scientific and clinical studies to establish a safe dosage of pharmacological preparations containing these metabolites, improve their bioavailability, and develop the foundations for the effectiveness of both extracts of plant materials and individual compounds.

In conclusion, it should be noted that PCs are valuable phytonutrients, contributing to the prevention and/or treatment of a broad spectrum of human diseases as well as protecting the body from various stressors. Their “multifaceted” impact (with over 40 types of biological activity), non-toxicity, and widespread distribution in functional foods and medicinal plants allow us to view these secondary metabolite compounds as factors that modify the biological response of the organism. They hold significant importance in protecting public health all over the world.

6. Conclusions and Future Perspectives

PCs are unique secondary metabolites that play a role in numerous physiological and biochemical processes within plants. They also exhibit high antioxidant activity, which has led to their successful utilization in pharmacology for treating diseases of various etiologies. The application of high-performance liquid chromatography, mass spectrometry, and other analytical methods has enabled the acquisition of new insights into the structure, properties, and biological activity of diverse constituents of phenolic metabolism. And this field requires further research due to the variety of chemical structures of PCs and the ability to form complexes with various metabolites. Biochemical and molecular-genetic research has refined our understanding of the various stages of PC biosynthesis, along with the enzymes, genes, and transcription factors engaged in these pathways. However, there is still a lack of clarity regarding the formation of proanthocyanidins, one of the preval‎ent PCs in plants that vary in their degree of polymerization. Our knowledge about the gene networks of phenolic metabolism and their functioning within plant cells is still insufficient. The examination and analysis of antioxidant activity in both plant extracts and individual phenolic compounds can be regarded as one of the actively developing areas in plant biology, physiology, and pharmacological medicine. In this context, the ecological aspect of these studies is of great significance, considering the substantial shifts in temperature regimes, light, and UV exposure and the accumulation of heavy metals on the planet. These changes may be a consequence of technological atmospheric pollution. All of these factors result in considerable changes in the life processes and productivity of plants, including the accumulation of phenolic bioantioxidants—crucial components for plant functional nutrition and the preservation of human health. The necessity of investigating the impact of these stress factors is beyond doubt. This research will allow us to “eval‎uate” the nature of their response and develop strategies to regulate the resistance and adaptation of plants to changing environmental conditions, including at the level of vital bioactive metabolites like PCs. Among the promising directions for further research is the production of nanoparticles, with PCs as important regulators of the vital activity of various organisms, including plants and humans. Despite significant progress in the study of plant PCs and their functional activity, there are still many unresolved issues that are of great interest to scientists of various specialties—chemists, biologists, geneticists, biotechnologists, pharmacists, physicians, and others. To a large extent, this is due to the regulation of the accumulation and composition of these biologically active metabolites in plants used for food and medicinal purposes for the health and preservation of the population.

Author Contributions

Drafting structure of the review, N.V.Z., M.Y.Z. and E.A.G.; review of draft structure, N.V.Z., M.Y.Z., T.L.N., V.V.K., E.A.G. and E.N.B.; writing original draft, N.V.Z., M.Y.Z., T.L.N., V.V.K. and E.A.G.; review and editing, N.V.Z., M.Y.Z., T.L.N., V.V.K., E.A.G., V.M.K., E.N.B. and M.A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by assignments 122042600086-7 (IPP RAS), 122042700002-6 (MBG RAS) and FGUM-2022-0003 (ARRIAB RAS) of the Ministry of Science and Higher Education of the Russian Federation.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Obata, T. Metabolons in plant primary and secondary metabolism. Phytochem. Rev. 2019, 18, 1483–1507. [Google Scholar] [CrossRef]
2. Salam, U.; Ullah, S.; Tang, Z.H.; Elateeq, A.A.; Khan, Y.; Khan, J.; Khan, A.; Ali, S. Plant metabolomics: An overview of the role of primary and secondary metabolites against different environmental stress factors. Life 2023, 13, 706. [Google Scholar] [CrossRef]
3. Erb, M.; Kliebenstein, D.J. Plant secondary metabolites as defenses, regulators, and primary metabolites: The blurred functional trichotomy. Plant Physiol. 2020, 184, 39–52. [Google Scholar] [CrossRef] [PubMed]
4. Elshafie, H.S.; Camele, I.; Mohamed, A.A.A. Comprehensive review on the biological, agricultural and pharmaceutical properties of secondary metabolites based-plant origin. Int. J. Mol. Sci. 2023, 24, 3266. [Google Scholar] [CrossRef] [PubMed]
5. Li, Y.; Kong, D.; Fu, Y.; Sussman, M.R.; Wu, H. The effect of developmental and environmental factors on secondary metabolites in medicinal plants. Plant. Physiol. Biochem. 2020, 148, 80–89. [Google Scholar] [CrossRef] [PubMed]
6. Qaderi, M.M.; Martel, A.B.; Strugnell, C.A. Environmental factors regulate plant secondary metabolites. Plants 2023, 12, 447. [Google Scholar] [CrossRef] [PubMed]
7. Šamec, D.; Karalija, E.; Šola, I.; Bok, V.V.; Salopek-Sondi, B. The role of polyphenols in abiotic stress response: The influence of molecular structure. Plants 2021, 10, 118. [Google Scholar] [CrossRef]
8. Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022, 383, 132531. [Google Scholar] [CrossRef]
9. Cheynier, V.; Comte, G.; Davies, K.M.; Lattanzio, V.; Martens, S. Plant phenolics: Recent advances on their biosynthesis, genetics, and ecophysiology. Plant Physiol. Biochem. 2013, 72, 1–20. [Google Scholar] [CrossRef]
10. Marchiosi, R.; dos Santos, W.D.; Constantin, R.P.; de Lima, R.B.; Soares, A.R.; Finger-Teixeira, A.; Mota, T.R.; de Oliveira, D.M.; Foletto-Felipe, M.; Abrahão, J.; et al. Biosynthesis and metabolic actions of simple phenolic acids in plants. Phytochem. Rev. 2020, 19, 865–906. [Google Scholar] [CrossRef]
11. Cao, Y.; Li, K.; Li, Y.; Zhao, X.; Wang, L. MYB transcription factors as regulators of secondary metabolism in plants. Biology 2020, 9, 61. [Google Scholar] [CrossRef] [PubMed]