경희대학교 의과대학·의학전문대학원

Ch. 27.

Biosynthesis

of the Nutritionally Nonessential Amino Acids

Ch. 28. Catabolism of Proteins & of Amino Acid

Nitrogen

Ch. 29. Catabolism of the Carbon Skeletons of Amino Acids

Ch. 30. Conversion of Amino Acids to Specialized Products

AMINO ACIDS METABOLISM

Car-bons

NH

2019 년 1 학기

Text : Harper’s Biochemistry Refs: Devlin’s, Lippincott’s

AMINO ACIDS METABOLISM

Car-bons

NH

Chapter 29.

* Transamination typically initiates amino acid catabolism

① Removal of α-amino nitrogen by transamination (Fig. 27-3, Fig. 28-6) is first catabolic reaction

except for Pro, Hyp, Thr, Lys

② Residual hydrocarbon skeleton  amphibolic intermediates (Fig. 29-1)

Figure 28-6 Transamination

Figure 27-3 Formation of alanine by transamination of pyruvate

Figure 29-1 Amphibolic intermediates formed from the carbon skeletons of amino acids

Alanine (Aspar-tate)

* Transamination typically initiates amino acid catabolism

① Removal of α-amino nitrogen by transamination (Fig. 27-3, Fig. 28-6) is first catabolic reaction

except for Pro, Hyp, Thr, Lys

② Residual hydrocarbon skeleton  amphibolic intermediates (Fig. 29-1) Glucogenic (글루코스 생성 )

amino acids

 Ketogenic (캐톤 생성 ) amino acids

 Both glucogenic and ketogenic amino acids

Figure 29-1 Amphibolic intermediates formed from the carbon skeletons of amino acids

*

글루코스생성 아미노산 (Glucogenic AAs)

•

_{케톤생성 아미노산 (Ketogenic AAs)}

*

Both glucogenic and ketogenic AAs

Figure 29-1 Amphibolic intermediates formed from the carbon skeletons of amino acids

•Transamination typically initiates amino acid catabolism

1) Asparagine, aspartate, glutamine, and glutamate

① Carbons of Asn and Asp

 oxaloacetate

② Carbons of Gln and Glu

 α-ketoglutarate(Fig. 29-2)

Figure 28-6 Transamina-tion

Figure 29-2 Catabolism of L-asparagine (top) and of L-glutamine (bottom) to amphibolic intermediates

1) Asparagine, aspartate, glutamine, and glutamate

Carbons of Asn and Asp

 oxaloacetate

Carbons of Gln and Glu

 α-ketoglutarate

1) Asparagine, aspartate, glutamine, and glutamate

Carbons of Asn and Asp

 oxaloacetate

Carbons of Gln and Glu

 α-ketoglutarate

Figure 29-3 Catabolism of proline (mitochondria)

2) Proline

① Pro  dehydroproline  glutamate-γ-semialdehyde  glutamate  α-ketoglutarate (Fig. 29-3)

② Metabolic block in type I hyperprolinemia : Pro dehydrogenase

③ Type II hyperprolinemia : glutamate- γ-semialdehyde dehydrogenase

type I hyperprolinemia

Figure 27-8 Biosynthesis of proline from glutamate

Proline

2) Proline

① Pro  dehydroproline  glutamate-γ-semialdehyde  glutamate 

α-ketoglutarate

(Fig. 29-3)

Figure 29-4 Catabolism of arginine

3) Arginine and ornithine

① Arg  ornithine  glutamate-γ-semialdehyde (Fig. 29-4)

Refer to Pro catabolism (Fig. 29-3)

Gluta-mate

α-ketoglutarate

Figure 29-3 Catabolism of proline (mitochon-dria)

Gyrate atrophy of the

retina

Figure 29-4 Catabolism of argi-nine

3) Arginine and ornithine

② Hyperornithinemia-hyperammonia syndromes: A defective mito. ornithine-citrulline antiporter

(Fig. 28-12) : impaired transport of ornithine into mitochondria for use in urea synthesis

Gluta-mate

Figure 29-5 Catabolism of L-histidine to a-ketoglu-tarate

4) Histidine

① His  urocanate  4-imidazolone-5-propionate N-forminoglutamate (Figlu)

 Glu (by formimino group transfer to tetrahydrofolate)  α-ketoglutarate(Fig. 29-5)

② In folic acid deficiency -> Figlu is excreted ③ Benign disorders:

histidinemia, urocanic aciduria associated with impaired histidase

*Catabolism of Glycine, Serine, Alanine, Cysteine, Threonine and 4-Hydroxyproline

① All of carbons of Gly, Ser, Ala, Cys, Thr, 4-Hyp form pyruvate  acetyl-CoA

Figure 29-1 Amphibolic intermediates formed from the carbon skeletons of amino acids

1) Glycine

① Gly cleavage complex of liver mito: splits Gly to CO₂ and NH₄+_{, and forms N}

5,N10-methylene THF (Fig. 29-6)

② Glycinuria : defect in renal tubular reabsorption

③ Defect in primary hyperoxaluria : failure to catabolize glyoxalate formed by deamination of glycine ④ Oxidation of glyoxalate to oxalate  urolithiasis, nephrocalcinosis, and early mortality

Figure 29-6 The glycine cleavage system of liver mitochondria

Glycine dehydrogenase (decarboxylating) Amino-forming aminomethyltrans-ferase Dihydrolipoamide dehydrogenase hyperoxaluria Glycine aminotransferase Glu or Ala ; Amino donor

2) Serine

① Ser to Gly by Ser hydroxymethyltransferase (Fig. 29-7)

② Ser catabolism  Gly , pyruvate

3) Alanine

① Transamination of Ala  pyruvate

② No known metabolic defect

Figure 29-7 Interconversion of serine and glycine by serine

hydroxymethyltrans-ferase

Figure 27-3 Formation of ala-nine

4) Cysteine

① Cystine to cysteine by cystine reductase (Fig. 29-8)

② Two different pathways : cysteine to pyruvate (Fig. 29-9)

Figure 29-8

The cystine reductase reaction

Figure 29-9 Catabolism of L-cysteine via the cysteine sulfinate pathway and by the 3-mercaptopyruvate pathway

Figure 29-8 The cystine reductase reac-tion

4) Cysteine

① Cystine to cysteine by cystine reductase (Fig. 29-8)

② Two different pathways : cysteine to pyruvate (Fig. 29-9)

③ Numerous abnormalities of Cys metabolism:  Cystine-lysinuria (cystinuria; benign);

* defects in renal absorption of AAs (Cys, Lys. Arg . Ornithine) * 신장의 근위세관 (proximal tubule) 에서

시스틴 , 라이신 , 아지닌 , 오니틴을 재흡수하는 체계가 결핍되어 일어나는 질환 .

* 시스틴을 재흡수하지 못하여 신장결석이 생성

 mixed disulfide of cysteine and homocysteine excreted by cystinuria patients is more soluble than cystine and reduces formation of cystine calculi

(시스틴 결석 ) (29-10)

Figure 29-10 Mixed disulfide of cysteine and homocysteine

4) Cysteine

① Cystine to cysteine by cystine reductase (Fig. 29-8)

② Two different pathways : cysteine to pyruvate (Fig. 29-9)

③ Numerous abnormalities of Cys metabolism:

 Cystine-lysinuria (cystinuria; 시스틴뇨증 ) (benign);  mixed disulfide of cysteine and homocysteine (29-10)

 Homocystinurias:

* deficiency in the reaction catalyzed by cystathionine β-synthase * osteoporosis ( 골다공증 ), mental retardation ( 정신지체 )

Figure 27-9 Conversion of homocysteine and serine

to homoserine and cysteine

cy

sta

thi

on

ine

β-sy

nth

as

e

Met

4) Cysteine

① Cystine to cysteine by cystine reductase (Fig. 29-8)

② Two different pathways : cysteine to pyruvate (Fig. 29-9)

③ Numerous abnormalities of Cys metabolism:

 Cystine-lysinuria (cystinuria; 시스틴뇨증 ) (benign);

 Cystine calculi ; mixed disulfide of cysteine and homocysteine (29-10)

 Homocystinurias:

* deficiency in the reaction catalyzed by cystathionine β-synthase

* osteoporosis, mental retardation  Cysinosis (cysteine storage disease):

* defective carrier-mediated transport of cystine * deposition of cystine crystals in tissues

* early mortality from acute renal failure ( 급성신부전 )

Figure 29-8 The cystine reductase reac-tion

Cysteine

Cys from Met (nutritionally essential AA): Met  SAM  homocysteine (Fig. 29-19)

L-Homecysteine + Ser  Cystathionine  L-Cys and homoserine (Fig. 27-9)

Figure 27-9 Conversion of homocysteine and serine to homoserine and cys-teine

cy

sta

thi

on

ine

β-sy

nth

as

e

Cysteine

Cys (nutritionally nonessential AA) from Met (nutritionally essential AA) : Met  SAM  homocys-teine (Fig. 29-19)

L-Homecysteine + Ser  Cystathionine  L-Cys and homoserine (Fig. 27-9)

Figure 27-9 Conversion of homocysteine and serine to homoserine and cys-teine

SAM

5) Threonine

① Thr  acetaldehyde + Gly and pyruvate

② Oxidation of acetaldehyde to acetate  formation of acetyl-CoA (Fig. 29-11)

Figure 29-11

Conversion of threonine to glycine and acetyl-CoA

pyruvate

Ser

Figure 29-7 Interconversion of

serine and glycine by serine hydroxymethyl-transferase

Figure 29-12 Intermediates in L-hydroxyproline catabolism

6) 4-Hydroxyproline

① Catabolism of Hyp  α-keto- γ-hydroxyglutarate

② An aldol-type cleavage  glyoxylate + pyruvate (Fig. 29-12)

③ hyperhydroxyprolinemia (benign) : A defect in hydroxyPro dehydrogenase

Type II hyperprolinemia

Figure 29-13 Intermediates in tyrosine catabolism

Additional AAs that form acetyl-CoA

1) Tyrosine

① Tyr  p-hydroxyphenylpyruvate  homogentisate  maleylacetoacetate  fumarylacetoacetate 

Figure 29-1 Amphibolic intermediates formed from the carbon skeletons of amino acids

Figure 29-13 Intermediates in tyrosine catabolism

Additional AAs that form acetyl-CoA

1) Tyrosine

Type I tyrosinemia (tyrosi-nosis) (reaction 4)

Type II tyrosinemia (Richner-Hanhart syn-drome) (reaction 1)

Neonatal tyrosinemia : lower p-hydroxyphenylpyruvate hydroxylase activity (reaction 2)

Additional AAs that form acetyl-CoA

1) Tyrosine

Alkaptonuria (reaction 3)

Alkaptonuria (1859, Garrod’s classic ideas of heritable metabolic disorder) : lack of homogentisate oxidase

: urine darkens due to oxidation of homogentisate

2) Phenylalanine

① Phe  Tyr (Fig 27-10)  subsequent reactions of tyrosine (Fig. 29-13)

② Hyperphenylalaninemias : defects in phenylalanine hydroxylase

(Type I, classic phenylketonuria or PKU), or in dihydrobiopterin re-ductase (Types II and III), or in dihydrobiopterin biosynthesis

(types IV and V)

③ Alternative catabolites (Fig. 29-14)

Figure 27-10 The phenylalanine hydroxylase re-action

phenylalanine hydroxylase

Figure 29-14 Alternative pathways of phenylalanine catabolism in

*

효소의 결핍 , 진단 , 페닐케톤뇨증의 치료

•

페닐케톤뇨증 (PKU):

-

페닐알라닌 하이드록실레이스의 결핍으로 인해 발병하는 질환 . 고페닐

알라닌혈증은 마찬가지로 하이드록실레이스의 보효소인 4 중 수소바이오

테린을 합성하거나 분해하는 효소의 결핍으로 인하여 생기는 질환 .

-

치료하지 않은 PKU 환자의 경우 정신지체 , 걸음 혹은 대화장애 , 간

질 , 과운동성 , 떨림 , 성장장애가 발생 .

-

신생아가 단백질을 섭취하기 시작한 후 48 시간에 채취한 혈액을 이용하

여 조기에 진단 .

-

치료는

페닐알라닌의 섭취 제한

.

2) Phenylalanine

② Hyperphenylalaninemias : defects in phenylalanine hydroxylase (Type I, classic phenylketonuria or PKU) , or in dihydrobiopterin reductase (Types II and III), or in dihydrobiopterin biosynthesis (types IV and V)

④ Diagnoses :

* Prenatal  DNA probes (Phe hydroxylase or dihydrobiopterin reductase), * Neonatal  FeCl₃ (detect urinary phenylpyruvate)

⑤ A diet low in Phe

Figure 29-15 Reactions and intermediates in the catabolism of L-lysine

3) Lysine

① Lys   crotonyl-CoA (Fig. 29-15) 

acetyl-CoA + CO₂ by the reactions of fatty acid catabolism

(Fig. 22-3)

② Hyperlysinemia:

elevated lysine (ornithine) inhibits liver arginase  hyperammonemia

Mitochon-dria

Figure 29-16 Catabolism of L-tryptophan

4) Tryptophan

① Trp via kynurenine-anthranilate pathway (Fig. 29-16)  N- L-formylkynurenine (by Trp oxygenase + O₂)  L-kynurenine

② Kynureninase require PLP and excretion of xanthurenate (Fig. 29-17)  diagnosis of vitamin B6 deficiency

③ Hartnup disease  impaired intestinal & renal transport of Trp ④ Pellagra-like signals and symptoms : Trp deficiency

Figure 29-18 Formation of S-adenosylmethionine

5) Methionine

Figure 29-19 Conversion of methionine to propionyl-CoA

5) Methionine

① Met + ATP  S-adenosylmethionine (SAM), “active Met” (Fig. 29-18)

② Met  SAM  S-adenosyl-L-homocysteine-> L-homocysteine -> Cystathione -> L-cysteine + α-ketoglutarate-> propionyl-CoA (Fig 29-19) and ultimately succinyl-CoA (Fig. 20-2)

methyl-

Malonyl-CoA

Succinyl-CoA

Citric acid cycle

Cysteine

Cys (nutritionally nonessential AA) from Met (nutritionally essential AA) : Met  SAM  homocys-teine (Fig. 29-19)

L-Homecysteine + Ser  Cystathionine  L-Cys and homoserine (Fig. 27-9)

Figure 27-9 Conversion of homocysteine and serine to homoserine and cys-teine

SAM

The Initial Reactions are Common to All Three Branched-chain Amino Acids Transamination , Oxidative decarboxylation (decarboxylase, a transacylase, and

a dihydrolipoly dehyrogenase  resembles pyruvate dehydrogenase), Dehydrogenation

Maple syrup urine

dis-ease

(branched-chain

ke-tonuria)

Figure 29-20 The analogous first three reactions in the catabolism of leucine, valine, and isoleucine

6. Metabolic Disorders of Branched-chain Amino Acid Catabolism

① Maple syrup urine disease (branched-chain ketonuria) <- defect in α-keto acid dehydrogenase complex

(reaction 2, Fig. 29-20) -> elevated plasma & urine levels of Leu, Ile, Val, α-keto acids, and α-hydroxy acids

@

효소 결핍 , 진단 , 단풍시럽뇨증의 치료

- 류신 , 아이소류신 , 발린을 탈카복시화 하는 효소인 가지사슬 - 케토산 디하이드로저네이스가 부분적이거나 완전하게 결핍되어 발병하는 질환 . – 이러한 아미노산과 그에 따른 α- 케토산은 혈중에 축적되어 뇌의 기능을 저해 . 증상 은 섭식 장애 , 구토 , 탈수 , 심각한 대사성 산증 , 뇨에서의 특징적인 냄새 . – _{만약 치료하지 않는다면 환자는 심각한 정신지체 , 물리적 운동장애를 겪게 되고 심지} 어는 죽음에까지 이름 . – _{이 질환은 생후 24 시간 이내의 혈액 샘플을 채취하여 진단 .} – _MSUD 환자는 류신 , 아이소류신 , 발린의 함량을 제한한 식이로 치료 .

The Initial Reactions are Common to All Three Branched-chain Amino Acids

* Subsequent catabolism of each AAs (Fig. 29-21, 22, 23)

Acetoacetate + Acetyl- CoA

Propionyl-CoA + Acetyl-CoA

(Fig. 29-22)

Succunyl-CoA

Chapter 30.

Conversion of Amino Acids to Specialized Products

Biomedical importance

① Modified amino acid in protein for a specific function

② Amino acid derivatives: heme, purines, pyrimidines, hormones,

neurotransmitters, and biological active peptides

③ Small peptides or peptide like molecules: histidine

④ Neurotransmitters and many drugs

α-amino acids

Alanine:

- _{Carrier of ammonia and of the carbons of pyruvate} from skeletal muscle to liver via cori cycle (Fig. 20-4)

Figure 28-3 The glucose-alanine cycle Fig 20-4 Cori cycle

Figure 28-4 Summary of amino acid exchange between organs immediately after feeding

glycogen glycogen

Figure 30-1 Arginine, ornithine, and proline metabolsm

α-amino acids

Arginine:

- formamidine donor for creatine synthesis (Fig. 30-12)

Figure 30-12 Biosynthesis of creatine

Figure 30-1 Arginine, ornithine, and proline metabolsm

α-amino acids

Arginine:

- formamidine donor for creatine synthesis (Fig. 30-12)

Figure 30-8 Intermediates and enzymes that participate in the biosynthesis of spermidine and spermine

Figure 30-8 Intermediates and enzymes that participate in the biosynthesis of spermidine and spermine

Methion-ine SAM

NH3

N

H

3

N

H

3

Figure 30-9 Catabolism of polyamines

Polyamin

e

oxidase

Polyamin

e

oxidase

Figure 30-1 Arginine, ornithine, and proline metabolsm

α-amino acids

Arginine:

- formamidine donor for creatine synthesis

- Ornithine Polyamine (putrescine spermine and spermidine )(Fig. 30-8)

Figure 30-2 The reaction catalyzed by phosphopantothenate-cysteine ligase

α-amino acids

Cysteine:

- _{biosynthesis of coenzyme A (Fig. 44-18) by forming 4-phosphopanthothenoyl-cysteine}

(Fig. 30-2)

- _{taurine  conjugates with bile acids (Fig. 26-7; Biosynthesis and degradation of bile acids)}

Figure 30-4 Biosynthesis of hippurate

α-amino acids

Glycine:

① Metabolites and pharmaceuticals excreted as water-soluble glycine conjugates:

glycocholic acid (Chap 26) and hippuric acid (Fig. 30-4) formed from the food additive bezoate

α-amino acids

Glycine:

① Metabolites and pharmaceuticals excreted as water-soluble glycine conjugates: glycocholic acid (Chap 26), hippuric acid (Fig. 30-4)

② Gly  incorporated into creatine(Fig. 30-12)

Figure 30-12 Biosynthesis of creatine and creati-nine Arg

SA

M

Glycine

Creatine

α-amino acids

Glycine:

① Metabolites and pharmaceuticals excreted as water-soluble glycine conjugates glycocholic acid (Chap 26), hippuric acid (Fig. 30-4)

② Gly  incorporated into creatine (Fig. 30-12)

③ Heme (Chap. 31)

- Nitrogen and a-Carbon are incorporated into pyrrole rings and methylene bridge carbons of heme ④ Purine biosynthesis (Fig. 33-1)

- Entire glycine molecule becomes atoms of 4,5, and 7 of purines

Figure 30-5 The reaction catalyzed by histidine decarboxylase

α-amino acids

Histidine

① Decarboxylation of His to histamine by broad specificity of aromatic L-amino acid decarboxylase (Dopa, 5-hydroxytryptophan, Phe, Tyr, and Trp) (Fig. 30-5) : 알레르기 반응 , 위산분비 , 모든 조직 에 존재 .

② Histidine compounds present in the human body ergothioneine, carnosine, and anserine (Fig. 30-6)

- Unknown functions,

- major constituents of excitable tissues, brain, and skeletal muscle ③ Wilson’s disease  low urinary levels of 3-methylHis

Figure 30-6 Derivatives of histidine

His-Figure 30-7 Biosynthesis of S-adenosylmethionine, cat-alyzed by methionine adenosyltransferase (MAT)

Methionine

①

S-Adenosylmethione :

methyl donor (Fig. 30-7)

- major nonprotein fate

- principal source of methyl group in the body

α-amino acids

SA

M

(Figure 29-19)

Methion-ine

Methionine

① S-Adenosylmethione : methyl donor (Fig. 30-7)

- major nonprotein fate

- principal source of methyl group in the body

②

Biosynthesis of polyamine: spermine and spermidine (

Fig. 31-4

)

α-amino acids

Spermidine and spemine : growth factors

(Fig. 30-8)

Catabolism of polyamines

(Fig. 30-9)

Figure 30-8 Intermediates and enzymes that participate in the biosynthesis of spermidine and spermine

Methion-ine SAM

NH3

N

H

3

N

H

3

Figure 30-9 Catabolism of polyamines

Polyamin

e

oxidase

Polyamin

e

oxidase

Serine

• Biosynthesis of

sphingosine (ceramide)

(Chap. 24)

• Biosynthesis of

purine , pyrimidines (Chap. 33)

- carbons 2 and 8 of purines

- methyl group of thymine

• Conversion of serine and homocysteine : cystathione β-synthase :

Cysteine

cy

sta

thi

on

ine

β-sy

nth

as

e

Met

Figure 27-9 Conversion of homocysteine and serine

to homoserine and cysteine

SAM

α-amino acids

Ser-ine

Cys-teine

Figure 30-10 Biosynthesis and metabolism of serotonin and melatonin

Tryptophan (Trp)

Trp  5-hydroxyTrp by Trp hydroxylase



serotonin (5-hydroxytryptamine)

by decarboxylation

(Fig. 30-10)

* serotonin : a potent vasoconstrictor, stimulator of smooth muscle contraction

α-amino acids

Serotonin

Tryptophan

5-OH

Trypto-phan

Trypto-phan

hydroxy-lase

Figure 30-10 Biosynthesis and metabolism of serotonin and melatonin

MAO

Melatonin

Serotonin

N-acetylation of serotonin

and O-methylation in pineal body

Tyrosine (Catecholamines)

* In neural cells, Tyr (L-dopa , dopamine)  norepinephrine and epinephrine (Fig. 30-11)

* In melanocytes, different enzyme hydroxylase Tyr (tyrosinase  melanin) * In adrenal medulla, phenylethanolamine-N-methyltransferase utilizes SAM  epinephrine

* Tyr is also precursor of triiodothyronine and thyoxine (Ch. 42)

Figure 30-11 Conversion of tyrosine to epinephrine and norepinephrine in neuronal and adrenal cells

α-amino acids

SA

M

Tyrosine

Dopa

Dopamin

e

Norepineph-rine

Epinephrine

Figure 30-12 Biosynthesis of creatine and creati-nine

Creatinine

① Creatinine in muscle from creatine

(Fig. 30-12)

② 24-hour urinary excretion of creatinine is proportionate to muscle mass

③

Gly, Arg, and Met

 creatinine biosynthesis

Arg

SA

M

Methionine

Creatine

Creatinine

Glycine

-

-alanine, -aminoisobutyrate,

γ-Aminobutyrate (GABA)

Non-α-amino acids

-alanyl dipeptides

: Activate myosin ATP ase

; Chelate copper

Figure 30-13 Metabolism of g-aminobutyrate

γ-Aminobutyrate

① γ-Aminobutyrate (GABA)

as inhibitory neurotransmitter

② Glu  GABA by

L-Glu decarboxylase

(

Fig. 30-13

)

③ Transamination of GABA  succinate semialdehyde



hydroxybutyrate (reduction)

or

succinate (oxidation)

Non-

α-amino acids

GABA

Glutamate

NH

Succinate

Hydroxybu-tyrate