고급 영양학 5장 단백질, 펩타이드, 아미노산에 대한 탐구의 기초

[문형철]

beyond reason

단백질, 펩타이드, 아미노산, 각종 효소, 보조효소, DNA는 모두 단백질(C, H, O, N)

아미노기(NH3), 카르복실기(COOH)와 관련되어 있음. 

20여개의 아미노산이 50여개 모여 폴리펩티드를 만들고 

폴리펩티드가 수소결합, 이온결합, 공유결합, 반데발스 힘 등으로 

1, 2, 3, 4차 단백질 구조를 만듬.

'이러한 구조는 기능을 결정한다'

기능을 결정하는 구조를 정상적으로 복구하는 것이 치료다

무엇이 구조를 정상적으로 복구할 수 있을까? 

1) 기쁨, 감사, 축복 540 이상의 의식수준

2) 오오라, 차크라, 기 에너지

3) 비타민, 미네랄, 치료적 보충제 등 미량원소

4) 음식에너지(ketone body)

5) 올바른 움직임

단백질에 대한 기초 영양학

Chapter 5단백질

1. 단백질의 일반적 특성

단백질은 신체의 기본적 구성성분, 생명의 기본물질, 중요한 영량영양소임. 

protein이라는 말은 '으뜸가는 것 to take the first place'라는 그리스어에서 유래됨. 

1) 단백질과 질소 동화작용

단백질은 여러가지 아미노산이 결합하여 합성됨. 사람은 20여가지 아미노산이 필요함. 식물은 공기중의 이산화탄소, 물, 암모니아, 질산염, 황산염을 이용하여 단백질을 합성하는데 이를 '질소 동화작용'이라고함. 사람은 식물처럼 질소 동화작용을 할 수 없기 때문에 섭취해야 함. 

2) 단백질의 원소조성

단백질은 C, H, O, N으로 구성되어 있으며 황, 철, 인을 함유한 것도 있음. 단백질의 종류에 따라서 질소, 수소, 산소, 탄소의 함량이 다름. 대개 탄소 51~55%, 산소 20~23%, 질소 15.5~18.7%, 수소 6~7%, 황 0.4~1.73%임. 

질소계수

단백질의 질소계수는 평균 16%임. 단백질을 분해하여 얻는 질소량에 6.25의 질소계수를 곱하면 단백질양을 산정할 수 있음. 

3) 단백질의 화학적 특성

단백질은 아미노산이 결합된 분자량이 큰 물질임. 일상 식품에는 22가지 아미노산이 발견되며 수십, 수백개의 아미노산이 결합되어 단백질이 합성됨. 단백질을 구성하는 기본단위인 아미노산은 '아미노기  NH2와 카르복실기 COOH를 가지고 있는 화합물임. 

# 아미노기(amino group) - 염기성, 유기화합물이 가지는 작용기의 하나. 질소원자에 수소가 결합된 형태(-NH2). 양전하와 결합하여 양전하를 띠는 양이온이 될 수 있고 질소원자가 가지고 있는 비공유 전자쌍 때문에 친핵체로 작용할 수 있음. 

# 카르복실기(carboxyl group) - 산성, 탄소, 수소, 산소로 이루어진 작용기의 하나로 -COOH  또는 -CO2H로 표시됨. 카르복실기 구조는 중심의 탄소원자에 하나의 산소원자가 이중결합으로 연결되어 있고 하나의 하이드록시기가 단일결합으로 연결되어 있음. 카복시기는 중심 탄소 원자에 하나의 최외각 전자를 지니고 있기 때문에, 보다 큰 분자와 결합할 수 있다. 하지만, 기본적으로 3 개의 결합을 필요로 하는 카복시기는 탄소 사슬의 끝부분에만 위치할 수 있다. 카복시기는 아세트산이 수소 이온을 방출해서 아세테이트가 되는 것처럼 수소 이온(H+)을 내놓아 산으로 작용할 수 있다.

아미노기와 카복시기를 모두 포함하고 있어, 아미노산은 중성에서 양쪽성 이온으로 존재하며, 카복실기가 공명 상태로 안정화를 취한다. 오른쪽의 구조에서 R은 나머지라는 뜻의 "Residue" 혹은 "Remainder"의 머릿글자로 곁사슬(Side chain)을 나타내고, 곁사슬에 무엇이 붙느냐에 따라 아미노산의 종류가 결정된다. 아미노산은 곁사슬의 성질에 따라 산성, 염기성, 친수성(극성), 소수성(무극성)의 네 가지 종류로 구분된다

단백질은 아미노산이 펩티드결합에 의해서 연결되어 합성됨. 

20여개의 필수(9가지), 비필수 아미노산(11가지)이 있고 

2개의 아미노산 연결 - 다이펩타이드

3개 연결 - 트리펩타이드

50여개 연결 - 폴리펩타이드

2. 아미노산의 특성과 분류

1) 아미노산의 특성

아미노산은 단백질의 구성단위로서 아미노산이 결합되어 단백질을 합성함. 아미노산의 화학적 구조내에 아미노기와 카르복실기를 가짐. 가장 간단한 아미노산은 글리신임.

아미노기는 염기성

카르복실기는 산성

따라서 아미노산은 산성용액에서는 아미노기(염기성)로 작용하고 

           염기성 용액에서는 카르복실기(산성)가 작용하여 체액을 약염기성으로 중화하는데 중요한 역할

대부분의 아미노산은 물에 잘 녹음

예외) 티로신, 시스틴은 물에 잘 녹지 않음. 프롤린은 알콜에 잘 녹음

2) 아미노산의 화학적 분류

아미노산은 R기의 화학적 조성에 따라 산성 아미노산, 중성 아미노산, 염기성 아미노산으로 분류됨. 

가. 중성 아미노산 : 그 구조내에 1개의 아미노기와 1개의 카르복실기를 가진 것

# neutral polar : tyrosine, serine, threonine, asparagine, glutamine, cysteine

# neutral nonpolar : tryptophan, phenylalanine, glycine, alanine, valine, isoleucine, leucine, methione, proline

나. 산성 아미노산 : R기에 카르복실기가 첨가된 것 - aspartic acid, glutamic acid

다. 염기성 아미노산 : R기에 아미노기가 첨가된 것 - lysine, arginine, histidine

중성 아미노산은 화학적 특성에 따라 지방족 아미노산, 곁가지 아미노산, 함황 아미노산, 방향족 아미노산으로 나뉨 

산성 아미노산 - 아스파트르산, 글루타민산

염기성 아미노산 - 리신, 아르기닌, 히스티딘

중성 아미노산 - 지방족 아미노산 - 글리신, 세린, 트레오닌, 아스파라긴, 글루타민, 알라닌, 프롤린

                        곁가지 아미노산 - 발린, 류신, 이소류신

                        함황 아미노산 - 시스테인, 메티오닌

                        방향족 아미노산 - 페닐알라닌, 티로신, 트립토판

3) 필수아미노산과 비필수 아미노산

체내에서 합성되지 못하거나 필요량보다 적게 합성되는 아미노산은 필수 아미노산

체내에서 충분한 양이 합성되는 아미노산을 비필수 아미노산

필수 아미노산 

히스티딘, 이소류신, 아르기닌, 메티오닌, 류신, 리신, 페닐알라닌, 트레오닌, 트립토판, 발린. 

  이중에서 '아르기닌과 히스티딘'은 아동기에는 필수, 성인기에는 비필수 아미노산

비필수 아미노산 - 아미노산의 탄소골격은 아미노산, 탄수화물, 지질에서 생성되며 여기에 아미노기가 다른 아미노산에 분리된 것이 합해져서 만들어짐. 이러한 과정은 특정 효소와 조효소에 의해서 만들어짐. 

포도당생성 아미노산

피루베이트(포도당) <- 알라닌, 발린, 류신

3-phosphoglycerate(포도당) <- 세린, 시스테인, 글라이신

옥살로아세이트(구연산회로) <- 아스파라닌, 메티오닌, 트레오닌, 이소류신, 리신

알파-케토글루타레이트(구연산회로)<-페닐알라닌, 글루타민, 프롤린, 아르기닌

phosphoenolypyruvate+erythros 4 phosphate <- 페닐알라닌, 타이로신, 트립토판

ribos 5- phosphate <- 히스티딘

3. 단백질의 구조와 분류

단백질은 아미노산이 수십개, 수백개 결합하여 합성됨. 아미노산이 연결되어 폴리펩티드를 이루면서 여러 형태를 가지며 고유의 작용을 함. 

1) 단백질의 4가지 구조

가. 1차구조

1차구조는 아미노산의 종류와 배합순서가 결정되어 폴리펩티드 결합으로 이어진 구조를 이룸. 아미노산의 결합순서는 단백질마다 다름. 헤모글로빈, 인슐린, 콜라겐 등 대부분의 단백질 분자는 10~15가지의 아미노산을 함유하고 있음. 인슐린은 한가닥의 폴리펩티드 사슬이 2개의 이황화 결합으로 연결된 구조임. 수십개 이상의 아미노산이 결합하여 폴리펩티드가 형성되면 이 폴리펩티드 사슬간에 이황화 결합(Disulfide bond)으로 이루어진 폴리펩티드가 형성되어 이 폴리펩티드를 안정화함. 

나. 2차구조

1차 구조로 생긴 폴리펩티드 사슬이 2차 구조인 나선구조 알파나, 병풍구조 베타를 이룸. 이러한 결합은 폴리펩티드 사슬내에서 또는 폴리펩티드 사슬간의 수소결합에 의해 안정화됨

다. 3차구조

3차구조는 폴리펩티드 사슬이 떨어져 있는 아미노산 잔기들과 여러가지 상호작용 결과 구조가 서로 접히고 꼬임으로써 생리작용을 완수할 수 있는 특수한 단백질 구조를 이룸. 섬유형 단백질과 구형 단백질이 있음. 

라. 4차구조

4차구조는 두개 이상의 폴리펩티드나 단백질이 수소결합과 같은 상호작용으로 연결되어 한 분자의 구조적 기능단위를 형성함. 헤모글로빈은 두쌍의 소단위로 구성되며 네개의 폴리펩티드로 이루어짐. 

2) 단백질의 화학적 분류

가. 단순 단백질

단순단백질은 가수분해에 의해서 단순 아미노산과 그 유도체를 생성함. 

알부민 - 달걀 알부민, 혈청 알부민, 밀의 류코신, 완두콩의 레구멜린

글로불린 - 근육과 혈청 글로불린, 콩의 글리신, 완두콩의 레구민, 감자의 투버린, 땅콩의 아라긴

글루텔린 - 밀의 글루테닌, 쌀의 오리제닌

프롤라민 - 밀의 글리아딘, 옥수수의 제인, 보리의 호르데인

알부미노이드 - 뼈의 콜라겐, 모발의 케라틴

히스톤 - 혈액의 글로빈, 흉선의 히스톤

프로타민 - 연어 정액중의 실민, 정어리 정액중의 클루페인

Albumin in critically ill patients: controversies and recommendations 

Haroldo Falcão^I,II; André Miguel Japiassú^I,III

^IHospital Quinta D´Or, Labs D'Or Network - Rio de Janeiro (RJ), Brazil
^IIIntensive Care Unit of Hospital Central da Polícia Militar do Estado do Rio de Janeiro – Rio de Janeiro (RJ), Brazil
^IIIIntensive Care Unit of Instituto de Pesquisa Clínica Evandro Chagas - FIOCRUZ – Rio de Janeiro (RJ), Brazil

Corresponding author

---

ABSTRACT 

Human albumin has been used as a therapeutic agent in intensive care units for more than 50 years. However, clinical studies from the late 1990s described possible harmful effects in critically ill patients. These studies' controversial results followed other randomized controlled studies and metaanalyses that showed no harmful effects of this colloid solution. In Brazil, several public and private hospitals comply with the Agência Nacional de Vigilância Sanitária (the Brazilian Health Surveillance Agency) recommendations for appropriate administration of intravenous albumin. This review discusses indications for albumin administration in critically ill patients and analyzes the evidence for metabolic and immunomodulatory effects of this colloid solution. We also describe the most significant studies from 1998 to the present time; these reveal an absence of incremental mortality from intravenous albumin administration as compared to crystalloid solutions. The National Health Surveillance Agency indications are discussed relative to the current body of evidence for albumin use in critically ill patients. 

Keywords: Albumin; Edema; Sepsis; Hypovolemia; Colloid osmotic pressure; Hypoalbuminemia; Therapeutics; Prognosis

알부민의 기능

1) intravascular pressure 유지

2) 산-염기 평형유지

3) 항산화작용

4) drug 운반

5) 영양소 운반(지방산, 빌리루빈, 호르몬 등)

6) 항응고 작용

7) microvascular integrity

Go to:

Abstract

Human serum albumin (HSA) has been used for a long time as a resuscitation fluid in critically ill patients. It is known to exert several important physiological and pharmacological functions. Among them, the antioxidant properties seem to be of paramount importance as they may be implied in the potential beneficial effects that have been observed in the critical care and hepatological settings. The specific antioxidant functions of the protein are closely related to its structure. Indeed, they are due to its multiple ligand-binding capacities and free radical-trapping properties. The HSA molecule can undergo various structural changes modifying its conformation and hence its binding properties and redox state. Such chemical modifications can occur during bioprocesses and storage conditions of the commercial HSA solutions, resulting in heterogeneous solutions for infusion. In this review, we explore the mechanisms that are responsible for the specific antioxidant properties of HSA in its native form, chemically modified forms, and commercial formulations. To conclude, we discuss the implication of this recent literature for future clinical trials using albumin as a drug and for elucidating the effects of HSA infusion in critically ill patients.

Keywords: 

Specific antioxidant properties of human serum albumin

Myriam Taverna,^1,2 Anne-Lise Marie,^1,2 Jean-Paul Mira,^3,4,5 and Bertrand Guidet^6,7,8

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Abstract

Human serum albumin (HSA) has been used for a long time as a resuscitation fluid in critically ill patients. It is known to exert several important physiological and pharmacological functions. Among them, the antioxidant properties seem to be of paramount importance as they may be implied in the potential beneficial effects that have been observed in the critical care and hepatological settings. The specific antioxidant functions of the protein are closely related to its structure. Indeed, they are due to its multiple ligand-binding capacities and free radical-trapping properties. The HSA molecule can undergo various structural changes modifying its conformation and hence its binding properties and redox state. Such chemical modifications can occur during bioprocesses and storage conditions of the commercial HSA solutions, resulting in heterogeneous solutions for infusion. In this review, we explore the mechanisms that are responsible for the specific antioxidant properties of HSA in its native form, chemically modified forms, and commercial formulations. To conclude, we discuss the implication of this recent literature for future clinical trials using albumin as a drug and for elucidating the effects of HSA infusion in critically ill patients.

Keywords: Human serum albumin, Antioxidant force, Oxidized albumin, Critically ill patients

나. 복합 단백질

핵단백질 - 핵산과 단백질이 결합된 것으로 세포핵의 주성분. 흉선의 뉴클레오히스톤, 어류 정액의 뉴클레오프로타민, 핵산 RNA와 DNA

당단백질 - 당질 또는 그 유도체와 단백질이 결합한 것. 우유의 카세인과 달걀 노른자의 오보비텔린

지단백질 - 킬로미크론, LDL, VLDL, HDL. 달걀 노른자의 리포비텔린과 리포베틸리닌

색소단백질 - 색소와 단백질이 결합된 것. 체내의 산화 환원에 중요한 역할. 헤모글로빈, 미오글로빈

미오글로빈 - 체조직 내 카탈라아제나 퍼옥시다아제 등의 산화효소, 플라보프로테인, NAD(니코틴아미드아데닌 디뉴클레오티드)

금속단백질 - 철, 구리, 아연과 단백질이 결합된 것. 철단백질 페리틴, 구리단백질 헤모시아닌, 연체동물의 혈액내 아연단백질인 인슐린(췌장호르몬), 마그네슘 함유의 클로로필 프로테인

참고) 헤모시아닌- 해양무척추동물이 산소 운반체로 쓰는 금속단백질(헤모글로빈과 달리 구리를 가짐)

참고) 클로로필 - 엽록소. 일종의 포르피린 화합물이며 헤모글로빈이 철을 함유하는 대신 마그네슘 함유

참고) Glycoproteins are proteins which contain oligosaccharide chains (glycans) covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or post-translational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

다. 유도 단백질

유도단백질은 단순단백질 또는 복합단백질이 산, 알칼리, 효소의 작용이나 가열에 의해 변성된 것을 말하며 변화정도에 따라 1차 유도단백질과 2차 유도단백질로 나뉨.

# 1차 유도단백질 - 파라카세인, 젤라틴, 응고단백질

# 2차 유도단백질 - 1차 유도단백질이 가수분해되어 생성된 것으로 프로테오스, 펩톤, 펩티드 

3) 단백질의 영양적, 형태적 분류

가. 영양적 분류

# 완전 단백질 - 정상적 성장을 돕고 체중을 증가시키며 생리적 기능을 도움. 이는 완전단백질이 모든 필수아미노산을 충분히 함유하고 있기 때문임. 완전 단백질에 속하는 단백질은 우유의 카세인과 락트알부민, 달걀의 오브알부민, 콩의 글리시닌, 보리의 에데스틴, 밀의 글루테닌과 글루텔린

# 부분적 불완전 단백질 - 성장을 돕지는 못하지만 체중을 유지시키는 작용. 이 단백질에는 밀의 글리아딘, 보리의 호르데인, 귀리의 프롤라민

# 불완전 단백질 - 단백질 급원으로 이것만 섭취하면 성장 지연, 체중감소하는 단백질. 젤라틴, 옥수수의 제인 등이 그것임. 

나. 형태적 분류 

# 구상 단백질 - 구형으로 소수성 및 친수성 상호작용에 의해 전체적으로 구형구조임. 구상 단백질은 수용성으로 대부분의 효소, 단백호르몬과 혈장 단백질 등이 그 예임. 구상 단백질 중 영양적으로 중요한 것은 '카세인, 달걀 알부민, 혈청 알부민과 글로불린, 헤모글로빈, 생리활성물질 등

# 섬유상 단백질 - 물에 용해되지 않으며 세포조직의 유지나 구조를 이루는 물질. 콜라겐, 엘라스틴, 명주실의 피브로인 등

참고) 글루텐 단백질의 구조

The protein gluten is found in wheat and grains such as rye and barley. Gluten is also involved with inducing an inflammatory response in individuals with celiac disease. Individuals who have the disease cannot digest gluten due to the structure of the protein, which will damage the small intestine. If an individual with celiac disease ingests foods containing gluten, the immune system responds by damaging the villi, which are fingerlike projections lining the small intestine. This immune response reduces the body’s ability to absorb nutrients that pass through the small intestine and into the bloodstream. As a result of the damaged villi, people with celiac disease can become malnourished. Although celiac disease is genetic, the research reviewed for this study placed emphasis on how the protein triggers an immune response in the gastrointestinal tract of affected individuals.

Gluten is a protein complex comprised of 2 components: gliadin (the water-soluble component) and glutenin (the water-isoluble component). Gliadins, for those with celiac disease, are the principle toxic component of gluten and are composed of proline and glutamine-rich peptide sequences. The peptides enter the circulatory system and come into contact with lymphocytes and T-cells, resulting in the release of cytokines. The cytokines interact with the villi of the small intestine and damage them, disabling the body from nutrient absorption. The symptoms can include abdominal pain, weight loss, fatigue, and many other symptoms associated with malnutrition. As of now, the only treatment for celiac disease is the total exclusion of gluten from the person’s diet.^[

4. 단백질의 소화와 흡수

단백질의 소화는 위와 소장에서 이루어짐. 단백질의 소화는 변성이 일어나서 단백질 2, 3, 4차 구조가 깨지고 폴리펩티드 사슬구조로 된 후 시작됨. 변성된 단백질에 소화효소가 작용하여 펩티드 결합이 분해되고 아미노산으로 완전 소화됨. 

참고) 폴리펩타이드는 50여개의 아미노산 연결

1) 소화

음식에 들어있는 단백질은 주로 위와 소장에서 소화가 이루어지며 분해된 아미노산은 소장에서 흡수되어 간으로 운반됨. 

There are several families that function in amino acid transport, some of these include:

• TC# 2.A.3 - Amino Acid-Polyamine-Organocation (APC) Superfamily
• TC# 2.A.18 - Amino Acid/Auxin Permease (AAAP) Family
• TC# 2.A.23 - Dicarboxylate/Amino Acid:Cation (Na⁺ or H⁺) Symporter (DAACS) Family
• TC# 2.A.26 - Branched Chain Amino Acid:Cation Symporter (LIVCS) Family
• TC# 2.A.42 - Hydroxy/Aromatic Amino Acid Permease (HAAAP) Family
• TC# 2.A.78 - Branched Chain Amino Acid Exporter (LIV-E) Family
• TC# 2.A.95 - 6TMS Neutral Amino Acid Transporter (NAAT) Family
• TC# 2.A.118 - Basic Amino Acid Antiporter (ArcD) Family
• TC# 2.A.120 - Putative Amino Acid Permease (PAAP) Family

Drug Des Devel Ther. 2017; 11: 3511–3517. 

Published online 2017 Dec 8. doi: 10.2147/DDDT.S151725

PMCID: PMC5726373

PMID: 29263649

Regulation profile of the intestinal peptide transporter 1 (PepT1)

Chun-Yang Wang,1,2 Shu Liu,1,2 Xiao-Nv Xie,1,2 and  Zhi-Rong Tan1,2

Author information Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Go to:

Abstract

The intestinal peptide transporter 1 (PepT1) was first identified in 1994. It plays a crucial role in the absorption of small peptides including not only >400 different dipeptides and 8,000 tripeptides digested from dietary proteins but also a repertoire of structurally related compounds and drugs. Owing to its critical role in the bioavailability of peptide-like drugs, such as the anti-cancer agents and anti-virus drug, PepT1 is increasingly becoming a striking prodrug-designing target. Therefore, the understanding of PepT1 gene regulation is of great importance both for dietary adaptation and for clinical drug treatment. After decades of research, it has been recognized that PepT1 could be regulated at the transcriptional and post-transcriptional levels by numerous factors. Therefore, the present review intends to summarize the progress made in the regulation of PepT1 and provide insights into the PepT1’s potential in clinical aspects of nutritional and drug therapies.

Keywords: PepT1, dietary, regulation, transport activity, absorption, bioavailability

가. 구강 및 위

단백질은 구강내에서 분해되지 않음. 저작작용과 침의 혼합으로 기계적으로 해체된 후 위에서 소화되기 시작함. 위에서는 단백질 소화효소인 펩신이 존재함. 펩신은 유문점막(주세포)에서 불활성 형태인 펩시노겐으로 분비됨. 불활성 펩시노겐은 염산의 작용으로 펩신으로 전환되어 활성을 가짐. 

펩신은 단백질 중 특정한 펩티드 결합부분을 가수분해함. 즉 글루탐산, 아스파르트산, 시스테인 등 산성 아미노산의 카르복실기와 페닐알라닌 또는 티로신 등 아미노기와의 펩티드 결합을 분해함. 펩신작용의 최적 pH는 1.5~2이므로 위내에서만 작용할 수 있음. 

Pepsin is an endopeptidase that breaks down proteins into smaller amino acids. It is produced in the chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, where it helps digest the proteins in food. Pepsin is an aspartic protease, using a catalytic aspartate in its active site.^[2]

It is one of two principal proteases in the human digestive system, the other two being chymotrypsin and trypsin. During the process of digestion, these enzymes, each of which is specialized in severing links between particular types of amino acids, collaborate to break down dietary proteins into their components, i.e., peptides and amino acids, which can be readily absorbed by the small intestine. Pepsin is most efficient in cleaving peptide bonds between hydrophobic and preferably aromatic amino acids such as phenylalanine, tryptophan, and tyrosine.^[3]

단백질은 위에서 일부만 소화되며 유미즙의 형태로 유문을 지나 십이지장으로 내려감. 소장내는 알카리성인 췌장액과 담즙이 분비되어서 유미즙의 pH가 6.5~7.5로 상승하여 펩신의 작용이 중단됨. 소장에서 각종 protease가 작용하여 아미노산으로 분해 흡수됨. 

Gastrointestinal pH profile in subjects with irritable bowel syndrome 

David Lalezari 

Cedar Sinai Medical Center, Los Angeles, CA, USA

Department of Gastroenterology, Cedar Sinai Medical Center, 
Los Angeles, CA, USA

Conflict of Interest: None

Correspondence to: David Lalezari, MD, Department of Medicine, St Mary-UCLA Medical Center, Long Beach, 90802, CA, USA, 
Tel.: +818 430 4000, Fax: +818 708 8142, 
e-mail: DrDLalezari@hotmail.com

Received 23 May 2012; accepted 2 July 2012

Abstract

Aim To investigate the small bowel pH profile and small intestine transit time (SITT) in healthy controls and patients with irritable bowel syndrome (IBS). 

Methods Nine IBS patients (3 males, mean age 35 yr) and 10 healthy subjects (6 males, mean age 33 yr) were studied. Intestinal pH profile and SITT were assessed by a wireless motility pH and pressure capsule (Smart Pill). Mean pH values were measured in the small intestine (SI) and compared both within and between groups. Data presented as mean or median, ANOVA, P <0.05 for significance. 

Results We found the pH for the first (Q1), second (Q2), third (Q3), and fourth quartile (Q4) of the SI in healthy versus IBS patients was 5.608 � 0.491 vs. 5.667 � 0.297, 6.200 � 0.328 vs. 6.168 � 0.288, 6.679 � 0.316 vs. 6.741 � 0.322, and 6.884 � 0.200 vs. 6.899 � 0.303, respectively. We found no significant group difference in pH per quartile (P=0.7979). The proximal SI was significantly more acidic, compared to distal segments, in both healthy subjects and IBS patients (P<0.0001). We found no significant difference in the measured SITT between IBS and control groups with a mean SITT of 218.56 � 59.60 min and 199.20 � 82.31 min, respectively (P=0.55).

Conclusion This study shows the presence of a gradient of pH along the SI, in both IBS and healthy subjects, the distal being less acidic. These finding may be of importance in small bowel homeostasis.

나. 소장

위에서 내려온 유미즙 즉 단백질은 소장에서 췌장액과 소장액에 있는 단백질분해 효소에 의해서 아미노산으로 완전히 가수분해됨. 유미즙이 소장으로 내려모면 소장벽에서 세크레틴이 분비되어 췌장액 분비를 촉진함. 소장(십이지장)에서 콜레시스토키닌이 분비되어 이 자극으로 췌장에서 트립시노겐과 키모트립시노겐이 불활성 형태로 분비됨. 소장에서 엔테로키나아제가 분비되어 트립시노겐은 트립신으로 활성화됨. 

단백질 분해효소(protease)

# 키모트립신 - 벤젠핵을 가진 아미노산(페닐알라닌, 티로신 등)의 카르복실기가 관여하고 있는 펩티드 결합에 작용

# 트립신 - 리신 또는 아르기닌(염기성 아미노산)의 카르복실기를 분해함. 염기성 아미노산의 카르복실기에 작용함. 이러한 효소들의 작용을 받아 단백질은 점차 분해되어 디펩티드로부터 저분자의 펩티드까지 다양한 종류의 펩티드로 분해됨

Trypsin (EC 3.4.21.4) is a serine protease from the PA clan superfamily, found in the digestive system of many vertebrates, where it hydrolyzes proteins.^[2][3] Trypsin is formed in the small intestine when its proenzyme form, the trypsinogen produced by the pancreas, is activated. Trypsin cleaves peptide chains mainly at the carboxyl side of the amino acids lysine or arginine.

# 카르복시펩티다아제 - 카르복실기가 말단을 이루는 끝부분에 작용하여 펩티드 결합을 끊어냄.

# 아미노펩티다아제 - 카르복실기 대신에 아미노기가 말달을 이루는 끝부분에 작용함. 이러한 효소들에 의해 연쇄의 끝부분으로부터 끊어내어 디펩티드만 남음

A carboxypeptidase (EC number 3.4.16 - 3.4.18) is a protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (C-terminal) end of a protein or peptide. This is in contrast to an aminopeptidases, which cleave peptide bonds at the N-terminus of proteins. Humans, animals, bacteria and plants contain several types of carboxypeptidases that have diverse functions ranging from catabolism to protein maturation.

Aminopeptidases are enzymes that catalyze the cleavage of amino acids from the amino terminus (N-terminus) of proteins or peptides (exopeptidases).They are widely distributed throughout the animal and plant kingdoms and are found in many subcellular organelles, in cytosol, and as membrane components. Aminopeptidases are used in essential cellular functions. Many, but not all, of these peptidases are zinc metalloenzymes.

# 디펩티다아제 - 디펩티드를 아미노산으로 분해함. 일부 펩티드는 흡수되어 소장벽내에서 아미노산으로 분해되기도 함. 

Dipeptidases are enzymes secreted by enterocytes into the small intestine. Dipeptidases hydrolyze bound pairs of amino acids, called dipeptides.

Dipeptidases are secreted onto the brush border of the villi in the small intestine, where they cleave dipeptides into their two component amino acids prior to absorption.

기관	비활성 전구체	활성 촉진물질	활성효소	소화작용
위	펩시노겐	위산	펩신 레닌(유아에서)	단백질 - 펩톤 카세인 - 응유
췌장	트립시노겐	엔테로키나아제	트립신	펩톤 내부의 알라닌, 라이신 -> 폴리펩티드, 디펩티드
	키모트립시노겐	활성 트립신	키모트립신	펩톤 내부의 Tyr, TrP ->폴리펩티드, 디펩티드
	프로카르복시펩티다제	활성 트립신	카르복시펩티다제	카르복시말단 -> 디펩티드, 아미노산
			아미노펩티다제	아미노말단 -> 펩티드, 디펩티드, 아미노산
소장			디펩티다제	디펩티드 -> 아미노산

2) 흡수 및 운반

단백질의 소화산물인 아미노산과 디펩티드는 소장상부에서 흡수함. 소장 전막세포는 융모를 형성하고 있으며 아미노산은 확산이나 에너지를 필요로 하는 능동수송을 통해 융모벽을 통과함. 

주의) 아미노산들이 능동수송 체계를 이용할때 유사구조를 가진 아미노산들이 같은 체계를 공유하게 되므로 특정 아미노산이 과다하게 많은 경우 다른 아미노산이 적게 흡수될 수 있음. 예를들어 다량의 아르기닌을 보충제로 복용하면 리신의 흡수가 저해될 수 있음. 

흡수된 아미노산은 모세혈관으로 운반되고 간문맥을 통해 간으로 이동하여 근육합성 또는 당신생에 활용됨. 

특이체질과 알레르기

특이체질을 가진 사람의 경우 특정 단백질이 아미노산으로 분해되지 않은 채로 소화관을 통과할 수 있음. 이 특정 단백질이 장벽을 통과하면 체내에서는 항체를 생성함. 후에 같은 단백질이 또 흡수되면 방어기능으로 알레르기 현상이 나타남. 특히 유아의 위장관은 미성숙한 상태이므로 큰 분자인 폴리펩티드를 그대로 흡수해서 알레르기 반응을 흔히 일으킴. 

What are IgE-mediated food allergies?

IgE-mediated food allergies cause your child’s immune system to react abnormally when exposed to one or more specific foods such as milk, egg, wheat or nuts. Children with this type of food allergy will react quickly — within a few minutes to a few hours. Immediate reactions are caused by an allergen-specific immunoglobulin E (IgE) antibody that floats around in the blood stream.

The most common food allergens include:

• Milk
• Egg
• Soy
• Wheat
• Peanut
• Tree nuts
• Fish
• Shellfish

All of these foods can trigger anaphylaxis (a severe, whole-body allergic reaction) in patients who are allergic.

Signs and symptoms of IgE-mediated food allergies

When your child has a food allergy, her body’s IgE antibodies identify that specific food as an invader and can produce symptoms in multiple areas of the body, including:

• Skin: “hives” (red blotches or welts that itch), mild to severe swelling
• Eyes: tearing, redness, itch
• Nose: clear discharge, itch, congestion
• Mouth: itch, lip swelling, tongue swelling
• Throat: tightness, trouble speaking, trouble inhaling
• Lungs: shortness of breath, rapid breathing, cough, wheeze
• Stomach: repeated vomiting, nausea, abdominal pain, diarrhea (usually later)
• Heart and circulation: weak pulse, loss of consciousness
• Brain: anxiety, agitation, loss of consciousness

Go to:

Abstract

This paper presents current views on the role of immunoglobulin G (IgG) antibodies in the reactions with food antigens in the digestive tract and their role in the diagnosis of food allergy based on the assays of specific IgG class antibodies, with a special focus on contemporary practice guidelines. In the light of current scientific knowledge, the IgG-specific antibody-mediated reactions are a body's natural and normal defensive reactions to infiltrating food antigens, which are considered as pathogens. On the other hand, specific IgG antibodies against food allergens play a crucial role in the induction and maintaining of immunological tolerance to food antigens. The statements of many scientific societies stress that sIgG are of no significant importance in the diagnosis of food allergy since their presence is associated with a normal immune response to food allergens and attests to a protracted exposure to food antigens.

Keywords: 

Role of immunoglobulin G antibodies in diagnosis of food allergy

Jacek Gocki and Zbigniew Bartuzi

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Abstract

This paper presents current views on the role of immunoglobulin G (IgG) antibodies in the reactions with food antigens in the digestive tract and their role in the diagnosis of food allergy based on the assays of specific IgG class antibodies, with a special focus on contemporary practice guidelines. In the light of current scientific knowledge, the IgG-specific antibody-mediated reactions are a body's natural and normal defensive reactions to infiltrating food antigens, which are considered as pathogens. On the other hand, specific IgG antibodies against food allergens play a crucial role in the induction and maintaining of immunological tolerance to food antigens. The statements of many scientific societies stress that sIgG are of no significant importance in the diagnosis of food allergy since their presence is associated with a normal immune response to food allergens and attests to a protracted exposure to food antigens.

Keywords: immunoglobulin G, food allergy, diagnosis

5. 단백질과 아미노산의 대사

1) 단백질 대사

단백질 대사는 체내에서 고유의 작용을 수행하기 위하여 아미노산 총량을 유지하며 이를 위해서 단백질 합성과 분해가 계속 일어남. 지방과 포도당은 잉여물질로 남으면 에너지로 저장하지만 단백질이 잉여로 남으면 체외로 배출됨. 

체내단백질 요약

단백질 대사가 활발하게 이루어지는 조직은 혈장, 췌장, 간, 신장, 근육 등임. 체내의 아미노산은 식품 단백질이 소화흡수되어 생성된 아미노산과 그리고 체조직의 분해로 생성되거나 체내에서 합성된 아미노산들임. 이러한 아미노산들과 간과 각 조직내의 아미노산 총량을 이룸. 

아미노산은 필요에 따라 체조직 단백질, 효소와 호르몬, 생리활성물질, 체지방을 합성하거나 에너지를 공급하는 등 다양하게 이용됨. 아미노산 분해로 생성된 탄소골격은 시트르산 회로로 들어가 에너지를 발생시킴. 이때 암모니아는 또 다른 아미노산 합성에 쓰이거나 요소로 합성됨.

외부 단백질 하루 70g

내인성 급원 단백질 하루 140g

과잉 아미노산 하루 0.9~10g 배설

2) 아미노산 분해

가. 탈아미노 반응(deamination)

단백질이 에너지를 발생하기 위해서는 먼저 아미노산에서 아미노기가 떨어져 나가는 탈아미노반응(deamination)이 일어나야 함. 그 결과 생성된 아미노기는 다른 물질로 이전되며 이를 아미노기 전이반응(transamination)이라고 함. 글루탐산탈수소효소에 의해서 탈아미노반응이 일어나 알파-케토글루타르산이 됨. 이때 NAD+ 조효소가 작용해야 함. 

탈아미노반응(deamination)으로 생성된 아미노산의 탄소골격은 탄수화물이나 지질이 분해되는 대사경로에 합류하여 시트르산 회로로 들어가 산화과정을 거쳐 에너지를 발생함. 

 참고) The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH₂)₂CO from ammonia (NH₃). This cycle occurs in ureotelic-organisms. The urea cycle converts highly toxic ammonia to urea for excretion.^[1] This cycle was the first metabolic cycle to be discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. This cycle was described in more detail later on by Ratner and Cohen. The urea cycle takes place primarily in the liver and, to a lesser extent, in the kidneys.

나. 아미노기 전이반응(transamination)

아미노기 전이반응은 비타민 B6가 조효소로 필요한 효소에 의해서 아미노기가 케토산에 전이되는 반응임. 대부분 천연에 존재하는 아미노산의 아미노기들은 전이반응 과정을 거쳐 새로운 아미노산을 형성함. 예로서 아스파르트산(아미노산)에서 알파-케토글루타르산으로 아미노기가 전이되어 옥살로아세트산과 글루탐산(아미노산)을 합성함. 이때 아미노기 전이효소가 아미노기를 전달하는 작용을 함. 

참고) 비타민 b6  피리독신 반감기 25-33일(15-22일)

Eighty to ninety percent of vitamin B6 in the body is found in muscles and estimated body stores amount to about 170 mg with a half-life of 25-33 days

다. 탈탄산반응(decarboxylation)

탈탄산반응은 아미노산이 비타민 B6를 조효소로 하는 탈탄산효소에 의해 탄산가스를 분리하여 아민이 생성되는 과정임. 생성된 아민은 도파민, 세로토닌, 카다베린, 가마-이미노부티르산(GABA)등으로 체내에서 유용하게 이용되며 일부 아민은 알레르기 반응을 일으키기도 함. 

Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO₂. GAD uses PLP as a cofactor. The reaction proceeds as follows:

HOOC-CH₂-CH₂-CH(NH₂)-COOH → CO₂ + HOOC-CH₂-CH₂-CH₂NH₂

In mammals, GAD exists in two isoforms with molecular weights of 67 and 65 kDa (GAD₆₇ and GAD₆₅), which are encoded by two different genes on different chromosomes (GAD1 and GAD2 genes, chromosomes 4 and 10 respectively).^[1][2] GAD₆₇ and GAD₆₅ are expressed in the brain where GABA is used as a neurotransmitter, and they are also expressed in the insulin-producing β-cells of the pancreas, in varying ratios depending upon the species.^[3] Together, these two enzymes maintain the major physiological supply of GABA in mammals,^[2] though it may also be synthesized from putrescine in the enteric nervous system,^[4] brain,^[5][6] and elsewhere by the actions of diamine oxidase and aldehyde dehydrogenase 1a1.^[4][6] Several truncated transcripts and polypeptides of GAD₆₇ are detectable in the developing brain,^[7] however their function, if any, is unknown.

• Article
• Open Access
• Published: 18 January 2019

Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

• Sebastiaan P. van Kessel, 
• Alexandra K. Frye, 
• Ahmed O. El-Gendy, 
• Maria Castejon, 
• Ali Keshavarzian, 
• Gertjan van Dijk & 
• Sahar El Aidy 

Nature Communications volume 10, Article number: 310 (2019) Cite this article

• 12k Accesses

• 29 Citations

• 166 Altmetric

• Metrics details

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

에너지 대사경로와 이에 따른 아미노산 분류

아미노산이 탈아미노반응 후 탄소골격이 시트르산 회로로 들어가는 경로는 포도당을 생성하거나 케톤을 생성하여 들어감. 각 아미노산의 에너지 대사경로는 아래와 같음.  대사경로를 따라 케톤체를 만드는 아미노산(케톤성 아미노산)과 포도당을 생성하는 아미노산(당원성 아미노산) 그리고 두가지를 모두 생성하는 아미노산으로 분류됨. 이들 모두 아세틸 CoA를 생성하지만 당원성 아미노산은 시트르산 회로의 중간물질이 되어 당합성(포도당, 글리코겐의 합성) 반응의 원료가 됨. 

케톤성 아미노산은 류신과 리신이며 그외는 탄소골격이 대사도중에 일부가 당원성이 됨. 최종적으로는 이들 모두는 탄산가스와 물로 산화, 분해되며 이 과정에서 에너지 화합물인 ATP 생성에 관여함. 

시스테인, 세린, 트레오닌 --> 피루브산 --> 옥살아세트산 --> 시트르산

이소류신, 류신, 트립토판 --> 아세틸  CoA --> 시트르산

류신, 리신, 티로신, 페닐알라닌, 트립토판 --> 아세토아세틸 CoA --> 아세틸 CoA --> 시트르산

아스파라긴, 아스파르트산 --> 옥살아세트산 --> 시트르산

티로신, 페닐알라닌, 아스파르트산 --> 푸마르산 --> 옥살아세트산 --> 시트르산

이소류신, 메티오닌, 발린 --> 숙신 CoA --> 푸마르산 --> 옥살아세트산 --> 시트르산

글루탐산, 글루타민, 히스티딘, 프롤린, 아르기닌 - 알파케토글루타르산 --> 숙신 CoA --> 푸마르산

아미노산	아민
3,4 -비스히드록시 페닐알라닌	도파민
히스티딘	히스타민
5, 히드록시 트립토판	세로토닌
리신	카다베린
글루타민산	감마-아미노부티르산 (GABA)

• Review
• Published: 30 November 2019

The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain

• Seong-Eun Lee, 
• Yunjong Lee & 
• Gum Hwa Lee 

Archives of Pharmacal Research volume 42, pages1031–1039(2019)Cite this article

• Abstract
  

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter that is required for the control of synaptic excitation/inhibition and neural oscillation. GABA is synthesized by glutamic acid decarboxylases (GADs) that are widely distributed and localized to axon terminals of inhibitory neurons as well as to the soma and, to a lesser extent, dendrites. The expression‎ and activity of GADs is highly correlated with GABA levels and subsequent GABAergic neurotransmission at the inhibitory synapse. Dysregulation of GADs has been implicated in various neurological disorders including epilepsy and schizophrenia. Two isoforms of GADs, GAD67 and GAD65, are expressed from separate genes and have different regulatory processes and molecular properties. This review focuses on the recent advances in understanding the structure of GAD, its transcriptional regulation and post-transcriptional modifications in the central nervous system. This may provide insights into the pathological mechanisms underlying neurological diseases that are associated with GAD dysfunction.

Tyrosine, Phenylalanine, and Catecholamine Synthesis and Function in the Brain 

John D. Fernstrom, Madelyn H. Fernstrom

The Journal of Nutrition, Volume 137, Issue 6, June 2007, Pages 1539S–1547S, https://doi.org/10.1093/jn/137.6.1539S

Published:

 

01 June 2007

• PDF
•  Split View
• Cite
• Permissions Icon Permissions
•  
  Share

   

Abstract

Aromatic amino acids in the brain function as precursors for the monoamine neurotransmitters serotonin (substrate tryptophan) and the catecholamines [dopamine, norepinephrine, epinephrine; substrate tyrosine (Tyr)]. Unlike almost all other neurotransmitter biosynthetic pathways, the rates of synthesis of serotonin and catecholamines in the brain are sensitive to local substrate concentrations, particularly in the ranges normally found in vivo. As a consequence, physiologic factors that influence brain pools of these amino acids, notably diet, influence their rates of conversion to neurotransmitter products, with functional consequences. This review focuses on Tyr and phenylalanine (Phe). Elevating brain Tyr concentrations stimulates catecholamine production, an effect exclusive to actively firing neurons. Increasing the amount of protein ingested, acutely (single meal) or chronically (intake over several days), raises brain Tyr concentrations and stimulates catecholamine synthesis. Phe, like Tyr, is a substrate for Tyr hydroxylase, the enzyme catalyzing the rate-limiting step in catecholamine synthesis. Tyr is the preferred substrate; consequently, unless Tyr concentrations are abnormally low, variations in Phe concentration do not affect catecholamine synthesis. Unlike Tyr, Phe does not demonstrate substrate inhibition. Hence, high concentrations of Phe do not inhibit catecholamine synthesis and probably are not responsible for the low production of catecholamines in subjects with phenylketonuria. Whereas neuronal catecholamine release varies directly with Tyr-induced changes in catecholamine synthesis, and brain functions linked pharmacologically to catecholamine neurons are predictably altered, the physiologic functions that utilize the link between Tyr supply and catecholamine synthesis/release are presently unknown. An attractive candidate is the passive monitoring of protein intake to influence protein-seeking behavior.

3) 요소회로와 질소배설물

아미노산의 분해, 즉 탈아미노반응 결과 떨어져 나온 질소는 암모니아를 형성함. 암모니아는 상당히 독성이 강하므로 독성이 없는 화합물인 요소로 전환, 배설하는 과정을 거침. 즉 각 조직세포에서 생성된 유독한 암모니아는 알라닌 형태로 되어 혈액을 통해 간으로 운반된 후 이산화탄소와 결합하여 무해한 요소로 전환되는데 이 과정을 요소회로(Urea cycle)라고 함. 

사람(척추동물)의 경우 요소는 요소회로에 의해 합성됨. 이 회로에 의해 합성되는 요소의 질소원자 또는탄소원자는 아스파르트산과 NH4+와 CO2에서 옴. 이 회로에서 탄소원자와 질소원자의 운반체 역할을 하는 화합물은 오르니틴임. 요소를 직접 생산하는 전구체는 아르기닌이며 이것은 아르기닌 가수분해효소의 작용에 의해 요소와 오르니틴으로 가수분해됨. 

다음반응은 시트룰린과 아스파르트산이 축합하여 아르기노숙신산이 합성되는 반응임. 마지막으로 아르기노숙신산 분해효소가 아르기노숙신산을 아르기닌과 푸마르산으로 분해함. 요소회로에서 푸마르산이 생성되어 시트르산 회로와 연결됨. 생성된 요소는 신장으로 가서 소변으로 배설됨 .

소변 중 질소 성분배설량은 단백질 섭취량에 따라 다름. 고단백 식이섭취 시에는 대부분 요소질소로 배설됨. 저단백 식이때보다 소변 중 총 질소와 요소배설량은 현저히 높음. 반면에 단백질 섭취량이 달라도 상대적으로 암모니아, 크레아틴 질소량은 변하지 않음. 기아시에도 질소량이 현저히 감소함. 간기능 이상으로 암모니아가 요소로 전환되지 못하면 혈중에 암모니아 농도가 높아지게 되어 중추신경계에 장애를 일으키는 간성혼수를 유발할 수 있음. 

4) 조직내 아미노산 대사

가. 주요조직의 아미노산 대사

식품단백질이 아미노산으로 완전히 소화된 후에 이 아미노산은 간문맥을 거쳐 간으로 운반되어 대사되고 일부는 다시 혈액으로 나와 각 조직에 운반되어 단백질 합성을 위해 사용됨. 

Hepatic Protein Metabolism

The main functions that the liver carries out in protein and amino acid metabolism include amino acids synthesis, interconversion and deamination, plasma protein synthesis, and urea synthesis. The liver is the only organ capable of eliminating nitrogen from amino acids via urea synthesis. Amino acid metabolism in the liver is finely regulated and the liver is the key organ for maintaining amino acid homeostasis in circulation. The liver can use amino acids for synthesis of glucose and key molecules [e.g., creatinine and glutathione (GSH)]. A general overview of amino acid metabolism in the liver is shown in Fig. 30.3.

# 간

간에서 혈장으로 유출되는 트립토판은 뇌로 가서 세로토닌 합성의 전구체로 사용됨. 곁가지 아미노산은 말초조직 특히 근육에서 분해됨. 육류를 섭취한 후에 간에서 방출되는 아미노산의 70%가 분지(곁가지) 아미노산임. 이는 육류단백질의 분지 아미노산은 간에서 분해가 잘 대사되지 않고 다른 아미노산들은 잘 분해되기 때문임. 이 분지 아미노산들은 근육에서 주로 분해됨. 

주요조직의 단백질 대사량

단백질 섭취량을 100g으로 볼때 장에서 분비되는 단백질을 합해서 흡수량은 160g임. 

체내 단백질 양을 보면 체단백질 합성량 250g, 근육 50g, 유리아미노산 100g, 간에서 25g, 적혈구, 백혈구 20g, 헤모글로빈 8g 순으로 이용됨. 흡수된 단백질 중 소변으로 88g정도 배설되며 피부로도 2g배설됨. 

# 근육

근육에서는 중성 아미노산인 알라닌과 글루타민이 주로 유출됨. 알라닌은 간으로 이동하여 포도당 신생과정을 거쳐 혈당으로 재방출되어 근육으로 다시 흡수됨(포도당-알라닌 회로). 글루타민은 장으로 이동하여 알라닌이 된 후 다시 간으로 이동함. 

참고) DNA replication

# 일반조직

발린, 류신, 이소류신은 분지 아미노산으로 일상생활에서 섭취해야 하는 필수아미노산의 50%를 차지함. 근육이나 뇌 등 일반조직에서 에너지원으로 사용되고 있음. 

나. 분지아미노산(branched-chain amino acid)의 대사

분지아미노산은 분지 아미노산 트랜스퍼라제에 의해 알파-케토산이 되고 산화적 탈산효소에 의해 분해되어 에너지 대사과정으로 들어감.

Nutr Metab (Lond). 2018; 15: 33. 

Published online 2018 May 3. doi: 10.1186/s12986-018-0271-1

PMCID: PMC5934885

PMID: 29755574

Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

Milan Holeček

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Go to:

Abstract

Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness.

In the article is demonstrated that the crucial roles in BCAA metabolism play: 

(i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; 

(ii) activity of branched-chain keto acid dehydrogenase (BCKD); and 

(iii) amination of branched-chain keto acids (BCKAs) to BCAAs. 

Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles.

The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes.

It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

Keywords: Cachexia, Ammonia, Glutamine, Diabetes, Cirrhosis, Nutrition

다. 함황 아미노산의 대사(sulfur amino acid)

황을 함유한 시스테인은 탈아미노반응 후 피르브산과 황산이 되며 글루타치온이나 타우린의 합성 전구체로서 중요함. 

메티오닌은 필수아미노산이며 지방간 예방인자임. 간에서 5-아데노실메티오닌(활성 메티오닌)이 되며 콜린합성에 관여함. 

Review Article | Open Access

Volume 2017 |Article ID 9584932 | 6 pages | https://doi.org/10.1155/2017/9584932

Oxidation Resistance of the Sulfur Amino Acids: Methionine and Cysteine

---

Peng Bin,^1,2 Ruilin Huang,¹ and Xihong Zhou¹

Show more

Academic Editor: Lidong Zhai

Received12 Sep 2017

Accepted20 Nov 2017

Published27 Dec 2017

Abstract

Sulfur amino acids are a kind of amino acids which contain sulfhydryl, and they play a crucial role in protein structure, metabolism, immunity, and oxidation. Our review demonstrates the oxidation resistance effect of methionine and cysteine, two of the most representative sulfur amino acids, and their metabolites. Methionine and cysteine are extremely sensitive to almost all forms of reactive oxygen species, which makes them antioxidative. Moreover, methionine and cysteine are precursors of S-adenosylmethionine, hydrogen sulfide, taurine, and glutathione. These products are reported to alleviate oxidant stress induced by various oxidants and protect the tissue from the damage. However, the deficiency and excess of methionine and cysteine in diet affect the normal growth of animals; thereby a new study about defining adequate levels of methionine and cysteine intake is important.

The sulfur-containing amino acids: an overview.

Brosnan JT1, Brosnan ME.

Author information

Abstract

Methionine, cysteine, homocysteine, and taurine are the 4 common sulfur-containing amino acids, but only the first 2 are incorporated into proteins. Sulfur belongs to the same group in the periodic table as oxygen but is much less electronegative. This difference accounts for some of the distinctive properties of the sulfur-containing amino acids. 

Methionine is the initiating amino acid in the synthesis of virtually all eukaryotic proteins; N-formylmethionine serves the same function in prokaryotes. Within proteins, many of the methionine residues are buried in the hydrophobic core, but some, which are exposed, are susceptible to oxidative damage. 

Cysteine, by virtue of its ability to form disulfide bonds, plays a crucial role in protein structure and in protein-folding pathways. Methionine metabolism begins with its activation to S-adenosylmethionine. This is a cofactor of extraordinary versatility, playing roles in methyl group transfer, 5'-deoxyadenosyl group transfer, polyamine synthesis, ethylene synthesis in plants, and many others. In animals, the great bulk of S-adenosylmethionine is used in methylation reactions. S-Adenosylhomocysteine, which is a product of these methyltransferases, gives rise to homocysteine. 

Homocysteine may be remethylated to methionine or converted to cysteine by the transsulfuration pathway. Methionine may also be metabolized by a transamination pathway. This pathway, which is significant only at high methionine concentrations, produces a number of toxic end products. 

Cysteine may be converted to such important products as glutathione and taurine. Taurine is present in many tissues at higher concentrations than any of the other amino acids. It is an essential nutrient for cats.

라. 지방족 아미노산(aliphatic amino acid)의 대사

세린과 트레오닌은 당단백질 중 당의 사슬과 단백질과의 결합을 하고 있는 아미노산으로 작용함. 세린은 피르브산의 모양으로 트레오닌은 프로피온산 혹은 아세틸  CoA의 형태로 시트르산 회로로 들어감. 이 두 아미노산은 글리신의 생합성 재료로도 중요함. 

마. 방향족 아미노산의 대사

방향족 고리를 포함하는 아미노산으로 20개의 아미노산중 페닐알라닌, 트립토판, 티로신, 히스티틴 등이 방향족 아미노산임. 페닐알라닌은 푸마르산, 아세트산으로 분해되며 티로신, 멜라닌, 아드레날린(부신피질 호르몬)등의 전구체로서 중요함. 페닐알라닌은 산화되어 티로신이 됨. 이 과정에 관여하는 효소가 결핍되면 페닐케톤뇨증이 됨. 페닐알라닌은 페닐피르브산이 되고 다시 분해되어 푸마르산이 되어 시트르산 회로로 들어감. 백피증은 페닐알라닌 대사이상으로 멜라닌 합성 대사경로의 효소결핍에 의한 질병이며 사람과 동물에서 나타남. 

그림) 방향족 아미노산의 대사

트립토판은 필수 아미노산이며 트립토판에서 세로토닌, 멜라토닌과 니코틴산 등이 합성됨. 

트립토판 대사

5) 단백질 합성

단백질 합성은 매우 효율적이고 연령에 따라 다름. 단백질 섭취량 당 합성량은 영아 5.3g, 성인 5.2g, 노인 4.5g임. 

가. 단백질 합성과 아미노산

아미노산은 세포와 조직에서 필요한 특정 단백질을 간에서 합성하기 위해 인체의 각 부분으로 이동됨. 필수 아미노산뿐만 아니라 비필수 아미노산도 단백질을 합성하기 위해 반드시 필요함. 단백질 합성에 필요한 모든 종류의 필수 아미노산은 반드시 각 조직에 공급되어야 함. 만약 필수 아미노산이 부족하면 단백질 합성이 일어나지 않음. 또한 특정 단백질 합성에 필요한 비필수 아미노산은 혈액에서 세포로 직접 공급되기도 하고 혹은 혈액에서 즉각 이용되지 못한다하더라도 세포에서 합성이 가능함. 이러한 비필수 아미노산의 형성은 아미노기 전이반응과정과 더불어 발생함. 가장 간단한 형태는 한 아미노산의 아미노기를 적당한 비질소 화합물에 이동시켜 아미노산을 합성하는 것임. 피리독신(vitamin B6)은 아미노기 전이반응을 돕는 비타민임. 

Go to:

Abstract

Vitamin B₆ (B₆) has a central role in the metabolism of amino acids, which includes important interactions with endogenous redox reactions through its effects on the glutathione peroxidase (GPX) system. In fact, B₆-dependent enzymes catalyse most reactions of the transsulfuration pathway, driving homocysteine to cysteine and further into GPX proteins. Considering that mammals metabolize sulfur- and seleno-amino acids similarly, B₆ plays an important role in the fate of sulfur-homocysteine and its seleno counterpart between transsulfuration and one-carbon metabolism, especially under oxidative stress conditions. This is particularly important in reproduction because ovarian metabolism may generate an excess of reactive oxygen species (ROS) during the peri-estrus period, which may impair ovulatory functions and early embryo development. Later in gestation, placentation raises embryo oxygen tension and may induce a higher expression‎ of ROS markers and eventually embryo losses. Interestingly, the metabolic accumulation of ROS up-regulates the flow of one-carbon units to transsulfuration and down-regulates remethylation. However, in embryos, the transsulfuration pathway is not functional, making the understanding of the interplay between these two pathways particularly crucial. In this review, the importance of the maternal metabolic status of B₆ for the flow of one-carbon units towards both maternal and embryonic GPX systems is discussed. Additionally, B₆ 

Pyridoxine (Vitamin B₆) and the Glutathione Peroxidase System; a Link between One-Carbon Metabolism and Antioxidation

Danyel Bueno Dalto^1,2 and Jean-Jacques Matte^1,*

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Abstract

Vitamin B6 (B6) has a central role in the metabolism of amino acids, which includes important interactions with endogenous redox reactions through its effects on the glutathione peroxidase (GPX) system. In fact, B6-dependent enzymes catalyse most reactions of the transsulfuration pathway, driving homocysteine to cysteine and further into GPX proteins. Considering that mammals metabolize sulfur- and seleno-amino acids similarly, B6 plays an important role in the fate of sulfur-homocysteine and its seleno counterpart between transsulfuration and one-carbon metabolism, especially under oxidative stress conditions. This is particularly important in reproduction because ovarian metabolism may generate an excess of reactive oxygen species (ROS) during the peri-estrus period, which may impair ovulatory functions and early embryo development. Later in gestation, placentation raises embryo oxygen tension and may induce a higher expression‎ of ROS markers and eventually embryo losses. Interestingly, the metabolic accumulation of ROS up-regulates the flow of one-carbon units to transsulfuration and down-regulates remethylation. However, in embryos, the transsulfuration pathway is not functional, making the understanding of the interplay between these two pathways particularly crucial. In this review, the importance of the maternal metabolic status of B6 for the flow of one-carbon units towards both maternal and embryonic GPX systems is discussed. Additionally, B6 effects on GPX activity and gene expression‎ in dams, as well as embryo development, are presented in a pig model under different oxidative stress conditions.

Keywords: glutathione peroxidase, one-carbon, pig, pyridoxine, remethylation, transsulfuration

2) 단백질 합성과정

단백질은 복잡한 메커니즘에 의해 합성됨. 단백질 합성에서 아미노산의 종류와 배합순서를 나타내는 유전정보는 DNA의 코드에 따라 전달됨. 실제 단백질 합성장소는 세포내의 리보솜이며 정보전달물질인 DNA에서 명시된 단백질이 합성되도록 함. 

단백질 합성을 단순화하면 다음 세 과정으로 구분할 수 있음. 

1단계 : DNA에서 세개의 염기로 된 코드그룹들이 각 아미노산을 합성하는 신호

2단계 : mRNA는 핵속 DNA에서 이 아미노산 코드가 전사되는 세포질로 운반

3단계 : mRNA는 리보솜에 부착하여 tRNA가 가지고 온 아미노산을 일렬로 연결하여 주므로 단백질이 합성됨. 

단백질 합성을 알기 쉽게 컴퓨터 자판으로 연상해 그림으로 나타낼 수 있음. 자판 세개가 한 아미노산이며 자판 세개를 치는 것은 여러가지 아미노산을 지칭함. 세개의 일정한 자판을 두드리면 아미노산의 순서가 정해지는데 이것은 mRNA때문임. 그러면 부호를 전달하여 움직여 주며 이 아미노산이 연결되어 단백질이 합성됨. 만약 페닐알라닌을 자판(코드)으로 부를때 롤러의 끝에 이 아미노산이 없으면 합성은 중지됨. 즉 필수아미노산과 비필수 아미노산 모두가 충분히 공급되어야만 체내에 필요한 단백질 합성이 가능함. 그러므로 영양소로서 아미노산과 단백질의 섭취가 중요함

Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, which balances the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a variety of critical functions as enzymes, structural proteins or hormones and therefore, are crucial biological components. As a result, protein synthesis is regulated at multiple steps ^[1]. Protein synthesis is very similar for prokaryotes and eukaryotes but there are distinct differences.

Protein synthesis can be divided broadly into two phases - transcription and translation. During transcription, a gene (section of DNA) is converted into a template molecule (messenger RNA) by enzymes, known as RNA polymerases, in the nucleus of the cell ^[2]. This mRNA is exported from the nucleus via nuclear pores to the cytoplasm of the cell for translation to occur. Subsequently during translation, the messenger RNA is read by ribosomes in the cytoplasm and the nucleotide sequence of the mRNA is used to determine the sequence of amino acids. The amino acids are joined together by peptide bonds (a type of covalent bond) to form a polypeptide chain.

Following translation of the mRNA into a polypeptide chain, this polypeptide chain must fold to form a functional protein i.e. fold to produce the functional active site of the enzyme. The incorrect folding of polypeptide chains can result in non-functional proteins, this is often caused by mutations in the underlying DNA nucleotide sequence. These mutations in the DNA change the subsequent mRNA sequence, which then changes the amino acid sequence in the polypeptide chain. These mutations can cause the mRNA sequence to be shorter due to earlier termination of transcription, thereby, producing a shorter polypeptide chain. Alternatively, the mutation can just missense mutation in the polypeptide chain ^[3].

A correctly folded protein may undergo further maturation through the addition of different post-translational modifications, which can alter the proteins ability to function, where the protein is located within the cell (e.g. cytoplasm or nucleus) and the proteins ability to interact with other proteins ^[4] .

Contents

• 1Transcription
  • 1.1Post-transcriptional modification
• 2Translation
• 3Protein Folding
  • 3.1Role of Protein Synthesis in Disease
• 4Post-translational modifications
  • 4.1Cleavage
  • 4.2Addition of chemical groups
  • 4.3Addition of complex molecules
  • 4.4Formation of covalent bonds
• 5See also
• 6References
• 7External links

Transcription[edit]

Main article: Transcription (genetics)

RNA polymerase transcribes the template strand of DNA to produce the complementary messenger RNA

Transcription occurs in the cell nucleus using DNA as a template to produce an RNA molecule. In eukaryotes, this RNA molecule is known as pre-mRNA as it undergoes post-transcriptional processing to produce a mature mRNA molecule. However, in prokaryotes post-transcriptional processing is not required so the mature mRNA molecule is immediately produced.

First, an enzyme known as a helicase acts on the molecule of DNA. DNA has an antiparallel, double helix structure composed of two, complementary polynucleotide strands, held together by hydrogen bonds between the base pairs. The helicase disrupts the hydrogen bonds causing a region of DNA - corresponding to a gene - to unwind, separating the two DNA strands and exposing a series of bases. Despite DNA being a double stranded molecule, only one of the strands acts as a template for pre-mRNA synthesis - this strand is known as the template strand. The other DNA strand (which is complementary to the template strand) is known as the coding strand.

The enzyme RNA polymerase then binds to the exposed template strand and reads from the 3-prime (3') end to the 5-prime (5') end. Simultaneously, the RNA polymerase synthesises a single strand of pre-mRNA (in the 5'-to-3' direction) through complementary base pairing with the exposed nucleotides on the template strand. The pre-mRNA molecule is built by the addition of single nucleotides by RNA polymerase as it moves along the DNA template strand, behind the RNA polymerase the two strands of DNA rejoin so only 12 base pairs on the DNA are exposed at a time ^[5].

The pre-mRNA molecule synthesised is complementary in sequence to the template DNA strand and shares the same nucleotide sequence as the coding DNA strand. However, there is one crucial difference in the nucleotide composition of DNA and RNA molecules. DNA is composed of 4 bases - guanine, cytosine, adenine and thymine (G, C, A and T) - RNA is also composed of 4 bases - guanine, cytosine, adenine and uracil. In RNA molecules, the DNA base thymine is replaced by uracil, therefore, in the pre-mRNA molecule, all complementary bases which would be thymines are replaced by uracil ^[6]. When RNA polymerases reaches a specific DNA sequence which terminates transcription, RNA polymerase detaches and pre-mRNA synthesis is complete.

Post-transcriptional modification[edit]

Maturation of pre-spliced mRNA through polyadenylation and addition of the 5' cap before undergoing splicing

Once transcription is complete, the pre-mRNA molecule undergoes post-transcriptional processing to produce a mature, functional mRNA molecule.

There are 3 key steps within post-transcriptional processing:

1. Addition of a 5' cap to the start of the pre-MRNA molecule
2. Addition of a 3' poly(A) tail is added to the end pre-mRNA molecule
3. Removal of introns from the pre-mRNA molecule via RNA splicing

The 5' cap is added to the 5' end (start) of the pre-mRNA molecule and is composed of a modified guanine nucleotide. The purpose of the 5' cap is to prevent the pre-mRNA and mature mRNA molecules from being broken down in the cell before they are translated, the cap also aids binding of the ribosome to the mRNA to start translation. In contrast, the 3' Poly(A) tail is added to the 3' end of the mRNA molecule. The Poly(A) tail is composed of a 100-200 adenine bases added by enzymes to the end of the pre-mRNA molecule ^[7].

This processed pre-mRNA molecule then undergoes the process of splicing. During splicing, nucleotide sequences known as introns are removed from the pre-mRNA molecule by a multi-protein complex known as a spliceosome (composed of over 150 proteins and RNA) ^[8] to produce the final, mature mRNA molecule. Genes are composed of a series of introns and exons, introns are nucleotide sequences within the gene that do not encode the protein while, exons are nucleotide sequences which directly encode a protein. Introns and exons are present in both the underlying DNA sequence and the pre-mRNA molecule but are removed by splicing to produce the final mRNA molecule. This mature mRNA molecule is then exported from the nucleus into the cytoplasm through nuclear pores in the envelope of the nucleus.

Translation[edit]

Main article: Translation (biology)

Translation process showing the cycle of tRNA addition and amino acid incorporation into the growing polypeptide chain

A ribosome is a biological machine that utilizes protein dynamics on nanoscales

Translation is the process of synthesising an amino acid polypeptide chain from the mRNA template molecule. In eukaryotes, translation occurs in the cytoplasm, where the ribosomes are located either free floating or attached to the endoplasmic reticulum. In prokaryotes, which lack a nucleus, the processes of transcription and translation both occur in the cytoplasm ^[9].

Ribosomes are complex molecular machines, made of a mixture of protein and RNA, arranged into two subunit (a large and small subunit), which surround the mRNA molecule. The ribosome reads the mRNA molecule in a 5'-3' direction and uses the mRNA as a template to determine the order of amino acids in the polypeptide chain ^[10]. In order to translate the mRNA molecule, the ribosome uses small molecules known as transfer RNAs (tRNA) to bring the correct amino acids to the ribosome. Each tRNA is composed of 70-80 nucleotides and adopts a characteristic cloverleaf structure due to the formation of hydrogen bonds between nucleotides within the molecule. ^[11] There are around 60 different types of tRNAs, which serve as adaptors in this process, each binds to a specific nucleotide sequence (known as a codon) in the mRNA molecule and delivering a specific amino acid.

The ribosome initially attaches to the mRNA at the start codon (AUG) and begins to translate the mRNA molecule using codon-anticodon base pairing. The mRNA nucleotide sequence is read in triplets - three adjacent nucleotides in the mRNA molecule correspond to a single codon. Each tRNA has an exposed sequence of three nucleotides, known as the anticodon, which are complementary in sequence to the codon on the mRNA molecule. For example, the first codon encountered on the mRNA molecule is the start codon, composed of the nucleotides AUG, the correct tRNA with the anticodon (complementary 3 nucleotide sequence UAC) binds to the mRNA using the ribosome. This tRNA delivers the correct amino acid corresponding to the mRNA codon, in the case of the start codon, the correct amino acid is methionine. The next codon (adjacent to the start codon) is then bound by the correct tRNA with complementary anticodon, delivering the next amino acid to ribosome. The ribosome then uses its enzymatic activity peptidyl transferase to catalyse the formation of the covalent peptide bond between the two adjacent amino acids ^[5].

The ribosome then moves along the mRNA molecule to the third codon, releasing the first tRNA molecule, as only two tRNA molecules can be brought together by a single ribosome at one time. The next complementary tRNA with the correct anticodon complementary to the third codon is selected for, delivering the next amino acid to the ribosome which is covalently joined to the growing polypeptide chain. This process continues with the ribosome moving along the mRNA molecule adding up to 15 amino acids per second to the polypeptide chain. Behind the first ribosome, up to 50 additional ribosomes can bind to the mRNA molecule and synthesise an identical polypeptide - this enables simultaneous synthesis of multiple identical polypeptide chains ^[5]. Termination of the growing polypeptide chain occurs when the ribosome encounters a stop codon (UAA, UAG, or UGA) in the mRNA molecule. When this happens, no tRNA can recognise it and a release factor induces the release of the polypeptide chain from the ribosome ^[11].

Protein Folding[edit]

Shows the process of protein folding from primary structure through to quaternary structure

Once synthesis of the polypeptide chain is completed by the ribosome, the polypeptide chain released and folds to adopt a specific structure which enables the protein to carry out its functions. The basic form of protein structure is known as the primary structure, which is simply the polypeptide chain i.e. a sequence of covalently bonded amino acids. The primary structure of a protein is encoded by a gene. Therefore, any changes to the sequence of the gene can alter the primary structure of the protein and all subsequent levels of protein structure ultimately changing the overall structure and function.

The primary structure of a protein (the polypeptide chain) can then fold or coil to form the secondary structure of the protein. The most common types of secondary structure are known as an alpha helix or beta sheet, these are small structures produced by hydrogen bonds forming within the polypeptide chain. This secondary structure then folds to produce the tertiary structure of the protein, this is its overall 3D structure which is made of different secondary structures folding together. In the tertiary structure, key protein features e.g. the active site, are folded and formed enabling the protein to function. Finally, whilst most proteins are made of a single polypeptide chain, however, some proteins are composed of multiple polypeptide chains (known as subunits) which fold and interact to form the quaternary structure. Hence, this is a multi-subunit complex composed of multiple folded, polypeptide chain subunits ^[12].

Role of Protein Synthesis in Disease[edit]

Many diseases are caused by mutations in genes, due to the direct connection between the genetic code of the gene and the amino acid sequence of the encoded protein. Changes to the primary structure of the protein can result in the protein mis-folding and unable to function. Mutations within a single gene have been identified as a cause of multiple diseases, including sickle cell disease, known as single gene disorders.

A comparison between a healthy individual and a sufferer of sickle cell anaemia showing the different red blood cell shapes and differing flow within blood vessels

Sickle cell disease is a group of diseases caused by a mutation in a subunit of haemoglobin, a protein found in red blood cells responsible for transporting oxygen, the most dangerous of these diseases is known as sickle cell anaemia. Sickle cell anaemia is the most common homozygous recessive single gene disorder, meaning the individual must carry a mutation in both copies of the gene to suffer from the disease. Haemoglobin is composed of four subunits - two A subunits and two B subunits. ^[13]. Patients suffering from sickle cell anaemia have a missense mutation in the haemoglobin B subunit gene. A missense mutation means the nucleotide mutation alters the overall codon triplet such that a different amino acid is paired with the new codon. In the case of sickle cell anaemia, the most common missense mutation is the single nucleotide mutation from thymine to adenine in the haemoglobin B subunit gene ^[14] which changes codon 6 from encoding glutamic acid to encoding valine ^[13].

This change in the primary structure of the haemoglobin B subunit alters the functionality of the haemoglobin multi-subunit complex in low oxygen conditions. When red blood cells unload oxygen into the tissues of the body, the mutated haemoglobin starts to stick together to form a semi-solid structure within the red blood cell. This distorts the shape of the red blood cell, resulting in the characteristic "sickle" red blood cell shape, and reduces flexibility. This rigid, distorted red blood cell can aggregate in blood vessels creating a blockage. The blockage prevents blood flow to the tissue and can lead to necrosis which causes pain to the individual ^[15].

Post-translational modifications[edit]

Completion of protein folding into the mature, functional 3D state is not necessarily the end of the protein maturation pathway. A folded protein can still undergo further processing in the form of post-translation modifications. There are over 200 known types of post-translation modification which can occur, these modifications can alter protein activity, the ability of the protein to interact with other proteins and where the protein is found within the cell e.g. in the cell nucleus or cytoplasm ^[16]. Through post-translational modification, the diversity of proteins encoded by the genome is expanded by 2 to 3 orders of magnitude^[17].

There are four key types of post-translational modification^[18]:

1. Cleavage
2. Addition of chemical groups
3. Addition of complex molecules
4. Formation of intramolecular bonds

Cleavage[edit]

Cleavage of proteins is an irreversible post-translational modification carried out by enzymes known as proteases. These proteases are often highly specific and cause hydrolysis of a limited number of peptide bonds within the target protein. The resulting shortened protein has new beginning and end of the amino acid chain. This post-translational modification often alters the proteins function, a cleaved protein can be rendered inactive or newly activated and can display new biological activities ^[19].

Addition of chemical groups[edit]

Following translation, small low molecular weight molecules can be added onto amino acids within the mature protein structure ^[20]. Examples of processes which add chemical groups to the target protein include methylation, acetylation and phosphorylation.

Methylation is the reversible addition of a methyl group onto an amino acid catalysed by an enzyme known as a methyltransferase. Methylation occurs on at least 9 of the 20 common amino acids, however, it mainly occurs on the amino acids lysine and arginine. One example of a protein which is commonly methylated is a histone, DNA is wrapped around histones in the nucleus, a highly specific pattern of histone methylation is used to control gene transcription in the nucleus ^[21].

Histone-based regulation of gene transcription is also modified by acetylation. Acetylation is the reversible covalent addition of an acetyl group onto a lysine amino acid, from a donor molecule known as acetyl coenzyme A, by the enzyme acetyltransferase^[22]. The nuclear proteins histones undergo acetylation on their lysine residues by enzymes known as histone acetyltransferase. The effect of acetylation is to weaken the interactions between the histone and DNA which makes more genes accessible for transcription ^[23].

The final, preval‎ent post-translational chemical group modification is phosphorylation. Phosphorylation is the reversible, covalent addition of a phosphate group to specific amino acids within the protein, mainly serine, threonine and tyrosine, by a protein kinase. Phosphorylation can drive proteins to interact with other proteins to produce a large, multi-protein complex ^[1].

Addition of complex molecules[edit]

Post-translational modification can incorporate more complex, larger molecules into the mature protein structure by covalently adding the molecule onto amino acids within the polypeptide chain. One common example of this is glycosylation, which is widely considered to be most common post-translational modification ^[17].

In glycosylation, a polysaccharide molecule (known as a glycan) is covalently added to a protein by enzymes known as glycosyltransferases and glycosidases in the cytoplasmic organelles the endoplasmic reticulum and Golgi apparatus. Glycosylation can have a critical role in determining the final, folded 3D structure of target protein - in some cases glycosylation of the protein is necessary for correct folding. N-linked glycosylation promotes protein folding by increasing solubility and mediates the protein binding to chaperones^[1].

There are broadly two types of glycosylation, N-linked glycosylation and O-linked glycosylation. N-linked glycosylation starts in the endoplasmic reticulum with the addition of a precursor glycan. The precursor glycan is modified in the Golgi apparatus to produce complex glycan bound covalently bound to the nitrogen atom on an asparagine amino acid within the polypeptide chain. In contrast, O-linked glycosylation is the covalent sequential addition of individual sugars onto the oxygen atom in the amino acids serine and threonine within the mature protein structure ^[1].

Formation of covalent bonds[edit]

Shows the formation of disulphide covalent bonds as a post-translational modification. Disulphide bonds can either form within a single polypeptide chain (left) or between polypeptide chains in a multi-subunit protein complex (right)

Many proteins produced within the cell are secreted outside of the cell, therefore, these proteins function as extracellular proteins. Extracellular proteins are exposed to a variety of conditions outside the cell. In order to stabilise the functional, 3D structure of the protein, covalent bonds are formed either within the protein or between the different polypeptide chains in a multi-subunit complex. The most preval‎ent type of covalent bond is a disulfide bond (also known as a disulfide bridge). A disulphide bond is formed between two cysteine amino acids using their side chain chemical groups containing a sulphur atom, known as thiol functional groups. Disulfide bonds act to stabilise the pre-existing conformation of protein. Disulfide bonds are formed in an oxidation reaction between two thiol groups and therefore, need an oxidising environment to react. As a result, disulfide bonds are typically formed in the oxidising environment of the endoplasmic reticulum catalysed by enzymes called protein disulfide isomerases. Disulfide bonds are rarely formed in the cytoplasm as it is a reducing environment ^[1]