Lehninger Principles of Biochemistry 5/eaging.pharm.pusan.ac.kr/lab/lecture/2011_2/L5 Ch18 aa... ·...
Transcript of Lehninger Principles of Biochemistry 5/eaging.pharm.pusan.ac.kr/lab/lecture/2011_2/L5 Ch18 aa... ·...
LEHNINGER PRINCIPLES OF BIOCHEMISTRY
Fifth Edition
David L. Nelson and Michael M. Cox
© 2008 W. H. Freeman and Company
CHAPTER 18 Amino Acid Oxidation and the
Production of Urea
Synthesis (nonessential amino acids)
Dietary proteins
Breakdown of tissue proteins
AMINO ACID POOL
Biosynthesis of tissue protein
Biosynthesis of small biomolecules
(purines, pyrimidines, biogenic amines, bile acids, etc.)
Degradation (approx. 1/3)
Degradation (approx. 2/3)
Excess amino acids Synthesis
Oxidative degradation: transamination
TCA intermediates
Acetyl CoA
Ketone bodies Fats
Glucose
CO2
Urea
Renal excretion
LUNGS
LIVER
KIDNEY
ALL BODY TISSUES GUT
*아미노산의 산화와 요소의 생성
• 동물에서의 amino acid(a.a) 산화조건
① 단백질이 분해되어 생성된 a.a이 새로운 protein합성에 필요치 않을 때
② a.a 과잉일 때 (∵ a.a은 저장×)
③ 당질을 이용할 수 없는 경우(기아 or 당뇨병) or 적절히 이용할 수 없을 때
• a.a 이화경로의 개요
• Urea cycle의 목적: N의 독성제거
• Amino group catabolism
• Protein의 소화
세포 내 protein
식이 protein
a.a
NH4+
Glu
α-ketoglutarate
탄소골격 α-keto acid
a.a, nucleotide, amine 생합성
Carbamoyl phosphate Urea cycle
Urea 95% urine
5% feces
TCA cycle CO2 + H2O + ATP
oxaloacetate glucose
TCA cycle의 Aspartate-Arginosuccinate shunt
< Overview of amino acid catabolism in mammals >
< Amino group catabolism >
< Amino group catabolism >
< Part of the human digestive(gastrointestinal) tract >
Secretin 분비 → 중화
• 대사에서의 a.a기
1. Transamination
1) a.a 전달반응
⇒ L-a.a의 NH3+기를 α-ketoglutarate에 전달하여 L-Glutamate 생성
2) PLP(pyridoxal phosphate)
: prosthetic group으로 pyridoxin or vitamin B6의 coenzyme type
① a.a전달효소의 활성자리에서 a.a기의 intermediate의 운반체
② α-carbon에서의 반응: Racemization, Decarboxylation, Transamination
⇒ α-carbon의 분해 → α-carbon에 “자유전자쌍” 존재 → 매우 불안정
→ PLP가 안정화시킴
transaminase α-ketoglutarate + L-a.a L-glutamate + α-keto acid
PLP
donor acceptor
Carboanion
< Enzyme-catalyzed transaminations >
Transamination
-NH3 전달
< Pyridoxal phosphate, the prosthetic group of aminotransferases >
< Pyridoxal phosphate, the prosthetic group of aminotransferases >
< Some amino acid transformations at the α carbon that are facilitated by pyridoxal phosphate >
Transamination
Racemization
Decarboxylation
< Reaction catalyzed by glutamate dehydrogenase >
< Ammonia transport in the form of glutamine >
< Glucose-alanine cycle >
( ALT = GPT )
Cori cycle과 협조
1. 조직장해측정법
: 혈중 중에 있는 각종 효소활성을 측정
① 간장질환 진단: ALT(GPT), AST(GOT)
⇒ 손상된 간세포로부터 혈류 중에 새어 나오므로
혈청 중 농도를 측정 → GPT, GOT검사
② Creatine kinase(CK): 심장 상해 시 최초로 혈중에 나타나는 심장효소
③ Lactate dehydrogenase(LDH): 손상 or 산소 결핍된 심근으로부터 나온다.
2. 대사에 있어서 amino acid의 역할
1) Glutamate
: 간에서 암모니아를 유리한다.
- Glutamate dehydrogenase (GD)
: isozyme으로서 ADP는 positive modulator, GTP는 negative modulator 임.
2) Glutamine
: 혈중에서 NH4+를 간 or 신장으로 운반한다. (NH4
+의 무독성 운반형)
3) Alanine
: NH4+를 근육에서 간으로 운반한다.
L-glutamate dehydrogenase
α-ketoglutarate + NH4+ Glutamate
NADP NADPH+H+
3. Glucose-Alanine Cycle
해당 Glucose Pyruvate
Alanine
혈당 혈중 Alanine
Glutamate
← alanine aminotransferase
α-ketogluatarate
NH4+
a.a
근육단백질
① 혼수상태, 뇌 장해 유발 ② 신경전달물질의 고갈에 영향 받음
NH4+의 유독성
Glucose Alanine
Pyruvate
Glucose 신생합성 α-ketogluatarate
← alanine aminotransferase
Glutamate NH4+ urea Urea cycle
4. 질소배설과 Urea cycle
1) NH4+ 배설에 따른 생물의 구분
① Ammonotelic (NH4+ 배설성): NH4
+ → amino nitrogen ex)수중생물
② Ureotelic (요소배설성): amino nitrogen → urea ex)육상동물
③ Uricotelic (요산배설성): uric acid로 배설 ex)조류, 파충류
2) Urea cycle과 amino기의 도입경로
3) Urea cycle과 TCA cycle의 연결
4) Carbamoyl phosphate synthetaseⅠ
N-acetylglutamate synthase에 의해 acetyl-CoA와 glutamate로부터 합성되는
N-acetylglutamate에 의해 allosteric enzyme 조절을 받아 활성화된다
∴ 2NH4+ + HCO3
- + 3ATP4- + H2O → urea + 2ADP3- + 4Pi2- + AMP2- + 5H+
< Urea cycle and reactions that feed amino groups into the cycle >
← Orn transcarbamoylase
← Arg-Succinate synthetase
Arginosuccinate lyase →
Arginase →
< Urea cycle and reactions that feed amino groups into the cycle >
(AST=GOT)
← Orn transcarbamoylase
< Urea cycle and reactions that feed amino groups into the cycle >
← Arg-Succinate synthetase
Arginase →
Arginosuccinate lyase →
< Links between the urea cycle and citric acid cycle >
< Synthesis of N-acetylglutamate and its activation of carbamoyl phosphate synthetase I >
고단백 섭취 시, 단식 시 증가
< N-acetyl-Glu synthase 결핍 시 치료제 >
< Nonessential and Essential Amino Acids for Humans and the Albino Rat >
< Treatment for deficiencies in urea cycle enzymes >
< Summary of amino acid catabolism >
Ketogenic
*Gluco/Ketogenic : Phe, Trp, Tyr, Ile, Thr
< Some enzyme cofactors important in one-carbon transfer reactions >
Vit B12
7. Cobalamin (Vitamin B12) A source of adenosylcobalamine, which is a cofactor of methylmalonyl-CoA mutase. This enzyme is involved in the exchange of the group –Co-S-CoA at C-2 of propionate with hydrogen atom at C-3, producing succinyl-CoA from L-methylmalonyl-CoA. Regulation of odd-number fatty acid and maturation factor of erythrocytes Pernicious anemia (악성빈혈) and secretion of methylmalonic acid in urea
Metabolism of odd-chain fatty acid
Methionine synthesis
Cobalamin (Vitamin B12)
< Conversions of one-carbon units on tetrahydrofolate >
< Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle >
Catabolic pathways for alanine, glycine, serine, cysteine, tryptophan, and threonine
Interplay of the pyridoxal phosphate and tetrahydrofolate cofactors in serine and glycine metabolism
Catabolic pathways for tryptophan, lysine, phenylalanine, tyrosine, leucine, and isoleucine
Tryptophan as precursor
Catabolic pathways for phenylalanine and tyrosine
Role of tetrahydrobiopterin in the phenylalanine hydroxylase reaction
Alternative pathways for catabolism of phenylalanine in phenylketonuria
Catabolic pathways for arginine, histidine, glutamate, glutamine, and proline
Catabolic pathways for methionine, isoleucine, threonine, and valine
Catabolic pathways for the three branchedchain amino acids: valine, isoleucine, and leucine
Catabolic pathway for asparagine and aspartate