Chapter 9Chapter 9

Catabolism of proteins 蛋白质分解代谢

Section 9.1Section 9.1

Nutritional function of proteins

Nutritional requirement Nutritional requirement of proteinsof proteins

• Nitrogen Balance 氮平衡 1. nitrogen balance: (normal adult) intake N = Losses N from the diet losses in urine and feces 2. Positive nitrogen balance: (children, preg

nant women, patients recovering) intake N > Losses N 3. Negative nitrogen balance: (starvation,

malnutrition, patients with fever) intake N < Losses N

Protein requirementProtein requirement

• After 8-10 days diets without proteins, the nitrogen excretion is 53mg/kg body weight per day. ( 20g proteins per day 60kg man.)

• The World Health Organization recommend 0.75g/kg body wt day-1 proteins from food.

• To Chinese diet: 80g per day a 65kg man.

• There is no storage of proteins in body, so proteins must be supplied every day.

• Excess diet protein can be used as energy supply.

Nutritional quality Nutritional quality of proteinof protein

• Essential Amino Acids are amino acids that cannot be synthesized by the body and must be obtained from diet. 必需 AAs

tryptophan( 色） phenylalanine （苯丙）

lysine （赖） threonine （苏） valine （缬） leucine （亮） isoleucine （异亮） methionine （蛋）• For infants and children: histidine （组） arginine （精）

• Non-essential Amino Acids are amino acids that can be synthesized by body. Which including the other 12 amino acids .

• Semi-essential Amino Acids can be synthesized in the body from essential amino acids.

tyrosine （酪） phenylalanine cysteine （半胱） methionine

Complementary Effect of DieComplementary Effect of Dietary Proteinstary Proteins （（互补作用互补作用））

• Quality of protein: the essential amino acid composition.

high quality: appropriate concentration of essential amino acids. (animal proteins)

• plant proteins: lack one or more of them.

• Complementary effect of dietary proteins: 蛋白质的互补作用

two or more plant proteins supplied together will complement each other to a higher quality.

Complementary Effect Complementary Effect of Dietary Proteinsof Dietary Proteins

Proteins origin

amount of lysine

amount of tryptophan

corn deficient rich

soybean rich deficient

together rich rich

Digestion, Absorption Putrefaction

DigestionDigestion of dietary of dietary proteinsproteins

• In stomach: pH of gastric juice < 2 function: kill microorganisms denature protein activate pepsinogen to pepsin.• Pepsin can hydrolyze peptide bonds to form large frag

ments and some free AA. coagulate milk (caseinogen casein)

胃蛋白酶原 胃蛋白酶

酪蛋白原 酪蛋白 凝 乳

In In smallsmall intestineintestine (main):(main):

• Proteolytic enzymes of pancreatic juice:

endopeptidases: cleave the internal peptide bonds.

trypsinase, chymotrypsin, elastase

exopeptidases: remove AAs from N- or C-terminal ends.

carboxypeptidase A and B

蛋白水解的

内肽酶

胰蛋白酶 糜蛋白酶 弹性蛋白酶

外肽酶

羧基肽酶

In In smallsmall intestineintestine

• Activation of zymogens from pancreas: enterokinase

trypsinogen trypsinase

chymotrypsinogen chymotrypsin proelastase elastase procarboxypeptidase carboxypeptidase

• Pancreatic proteolytic enzymes produce free amino acids and small peptides (2-8 AA residues.)

• Aminopeptidase hydrolyzes amino-terminal AA from oligopeptide.

• Dipeptidase hydrolyzes dipeptide.• The results of protein digestion: free AAs, dipeptides, tripeptides.

Products

Amino acids +

Free amino acidDigestion of protein

Dipeptidase

CarboxypeptidaseAminopeptidase endopeptidases

by transport systems: seven transport systems

Absorption and Absorption and transportation of AAtransportation of AA

Location: intestine

free amino acids,dipeptides,tripeptides

• The AA is absorbed with Na+, which has to be pumped out of the cell by a sodium pump ， which is an ATP-requiring process.

• The absorbed dipeptides and tripeptides are hydrolyzed to free AAs before they be transport into portal vein.

Absorption and Absorption and transportation of AAtransportation of AA

Putrefaction Putrefaction • The undigested proteins and no absorbe

d AAs pass into the large intestine, where the decomposition of which by bacteria is called putrefaction.

• Products: benefits: vitamin K, B12, folic acid, toxicoids: amines, phenol, indole, H2S,

胺 苯酚 吲哚 硫化氢

• Decarboxylation of AAs produces amines histidine histamine tyrosine tyramine lysine cadaverine• Tyramine can raise blood pressure, hista

mine and cadaverine can decrease blood pressure

• histamine can cause arteriolar dilatation• Production of Phenol: tyrosine phenol

尸胺酪胺组胺

小动脉扩张

• Production of indole: (odor of feces) tryptophan indole• Production of H2S cysteine hydrogen sulfide• Production of ammonia （氨） unabsorbed AA urea (from blood)

NH3

• The toxic products of putrefaction are removed by liver.

• If liver is damaged, which may cause the hepatic coma. （肝昏迷）

苯乙胺 苯乙醇胺

CH2

CH2NH2

CH2

CH2NH2 CH2NH2

C OHH

CH2NH2

C OHH

酪胺 β- 羟酪胺

CH2

CH2NH2

OH

CH2

CH2NH2

OH

CH2NH2

C OHH

OH

CH2NH2

C OHH

OH

Section 9.3Section 9.3

Degradation of Protein in Cells

• Protein turnover: 蛋白质转换 the degradation and synthesis of protein. 1%-2% of total body proteins turnover ea

ch day.

• Half time (t1/2 ): the time required to reduce the proteins concentration to 50% of its initial value.

HMG CoA reductase 0.5-1 hours plasma proteins 10 days collagen and histone several months胶原质 组蛋白

There are There are two pathwaytwo pathway to degrade protein in to degrade protein in cells.cells.

• Lysosomal pathway -extracellular; membrane-associated; lo

ng-lived proteins -ATP independent process -degraded by cathepsin (pH 5.0)

溶酶体

组织蛋白酶

• Cytosol pathway -abnormal, damaged, short-lived prote

ins -require ATP and ubiquitin 泛素 -degraded by proteosome (pH 7.8)

There are two pathway There are two pathway to degrade protein in to degrade protein in cells.cells.

蛋白酶体

• Ubiquitin: -76 amino acid residues -presents in all eukaryotic cells -the primary structure is highly conserved,• The process of ubiquitin pathway-ubiquitination: chains of 4 or more ubiqui

tin combine to the protein 泛素化-degradation of ubiqitinated protein

泛素 C O-

O

+ HS-E1

ATP AMP+PPi

泛素 C

O

S E1

HS-E2 HS-E1

泛素 C

O

S E2泛素 C

O

S E1

Ub

protein HS-E2

泛素 C

O

S E2 泛素 C NH protein

O

E3

ubiquitination

Ub

Ub

Ub

Ub

Ub

E1:ubiquitin activating enzyme,

E2: ubiquitin-conjugating enzyme,

E3: ubiquitin-protein ligase

Degradation

Ubn-CO-NH-protein

proteosome

Amino acids

Section 9.4Section 9.4

Amino Acid Catabolism: General

• Amino acid metabolic pool: 氨基酸代谢库 the amino acids coming from digesti

on and absorption of dietary proteins or from degradation of body proteins will be used equally in the body.

α-ketoacid

Deamin-

ation

Keto body

Energy

glucose

Amine

decaboxylation

NH3

urea

conversion

Non-protein nitrogen compounds

Dietary proteins

absorption

Tissue proteins

Amino acis Synthesis (non-essencial AAs)

Amino acid metabolic pool

Degradation

Source utilization

Body protein

synthesis

Deamination of AAs Deamination of AAs 脱氨基脱氨基

• Term: removal of the amino groups of AAs

• Including: -Oxidative deamination 氧化脱氨基 -Non-oxidative deamination 非氧化脱氨基 -Transamination 转氨基作用 -Coupling the transamination with deamination of glutamate -Purine nucleotide cycle 嘌呤核苷酸循环

1. Oxidative deamination1. Oxidative deamination• L-glutamate Dehydrogenase L- 谷氨酸脱氢酶-wide distribution, high activity (except muscle)-the major enzyme in the metabolism of AAs-inhibitors: GTP, ATP; activators: GDP, ADP

L-glutamate

NH3

α-ketoglutarate

NAD(P)+

NAD(P)H+H+

H2O

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH

C

(CH2)2

COOH

COOH

NH

C

(CH2)2

COOH

COOH

O

C

(CH2)2

COOH

COOH

+

O

C

(CH2)2

COOH

COOH

+

α- aminoglutarate

L-glutamate Dehydrogenase

2.Non-oxidative deamination2.Non-oxidative deamination

• Serine and threonine -the α-amino group of which can be remo

ved nonoxidatively -special dehydratases

• Cysteine -cysteine desulfhydrase

3.Transamination3.Transamination

• The transfer of α-amino group from a α-amino acid to a α-keto acid, then the α-amino acid forms a corresponding α-keto acid, the α-keto acid forms a corresponding α-amino acid. (except Lys, Thr and Pro )

Transami-nase

α-amino acid 2

α-amino acid 1

α-keto acid 2

α-keto acid 1

3.Transamination3.Transamination• The -amino group of most amino acids is t

ransferred to -ketoglutarate to form glutamate

-NH2 is only transferred from one of amino acids to a - keto acid, not really removed.

• Aminotransferases (transaminases) 转氨酶 -Different transaminate reactions are cataly

zed by different transaminases

Alanine transaminase (ALT, or GPT) and Aspartate transaminase (AST, or GOT)

Alanine + -ketoglutarate

pyruvate +Glutamate

Aspartate + -ketoglutarate

Oxaloacetate + Glutamate

ALT

AST

组织 GOT GPT

心 156000 7100

肝 142000 44000

骨骼肌 99000 4800

肾 91000 19000

组织 GOT GPT

胰腺

脾

肺

血清

28000 2000

14000 1200

10000 700

20 16

Tissue Tissue

Heart

Liver

Muscle

Kidney

Pancreas

Spleen

Serum

Lung

• The serum levels of GOT, GPT are very low normally.• Measure the serum level of special transaminase ha

s diagnostic significance.• Increase of GPT: liver damage (hepatitis)• Increase of GOT: heart damage (myocardial infarctio

n) 心肌梗塞

Mechanism of transaminationMechanism of transamination

• The cofactor of transaminase is pyridoxal phosphate 磷酸吡哆醛

1

Ketimine (Schiff base )

1

1

Pyridoxal phosphate

pyridoxamine phosphate

Amino acid

α-ketoacid

Aldimeine

(Schiff base )

R1

NH2

CHCOOH R1 C COOH

O

Transaminase

R2 C COOH

O

R2

NH2

CHCOOH

-amino acid -keto acid

Pyridoxal phosphate

pyridoxamine phosphate

4.Coupling the transamination 4.Coupling the transamination with deamination of glutamatewith deamination of glutamate

• The -amino group of most amino acids is transferred to -ketoglutarate to form glutamate by transamination.

• Then glutamate deaminated to ammonia and -ketoglutarate by glutamate dehydrogenase.

• Which is called coupling deamination.

NH3+NADH+H+

L- glutamate dehydrogenase

H2O+NAD+

transaminase

-ketoglutarate

glutamate

- amino acid

-keto acid

coupling deamination.

5.Purine Nucleotide 5.Purine Nucleotide CycleCycle

• The activity of L-glutamate dehydrogenase is low in the skeletal muscle and heart, where the major deamination process is purine nucleotide cycle.

Malate

(IMP)

3

glutamateα-keto-acid

1

Oxaloacetate

Aspartate

2

4

H2O

NH3

Fumarate

(AMP)

α-aminoacid

-keto-glutarate

Adenylo-succinate

4: AMP deaminase1: Transaminase

2: Aspartate transaminase(AST)

3: Adenylosuccinate synthetase

Metabolism of AmmoniaMetabolism of Ammonia

• Source of ammonia in blood --Endogenous source: 内源性 deamination of amino acids (major) catabolism of other nitrogen compound

s --Exogenous source: (4g/day) 外源性 production of putrefaction degradation of urea in large intestine by

bacteria

Transport of Transport of ammonia in bloodammonia in blood

• Only traces of ammonia (NH3) exist in blood.

• NH3 is toxic to the central nervous system. So it must be transport in nontoxic type.

transport as glutamine 谷氨酰胺 Alanine-glucose cycle 丙氨酸 - 葡萄糖循环

1.Fixes ammonia as 1.Fixes ammonia as glutamineglutamine

• catalyzed by glutamine synthetase.

• glutamine is the temporary non-toxic storage and transport form of NH3

•Synthesized in brain and muscle,

degraded in kidney and liver

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

L-glutamate

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH1NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

glutamine

NH3+ATP ADP+Pi

H2ONH3

Glutamine synthetase

glutaminase

2.Alanine-glucose 2.Alanine-glucose cyclecycle

protein

Amino acid

NH3

Glutamate

α-keto- glutarate

pyruvate

Muscle Blood

Alanine

glucose

α-ketoglutarate

Glutamatepyruvate

NH3

urea

Liver

glucose glucose

Alanine

Alanine

Formation of UreaFormation of Urea

• Urea is the major product of nitrogen.• Synthesized in liver, excreted by kidney.• The process is called urea cycle or ornithin

e cycle found by Hans Krebs.• To 1mol urea: 1mol ammonia 1mol α-amino nitrogen from aspartate 1mol CO2

3mol ATP

鸟氨酸循环

Process of urea cycleProcess of urea cycle

• 1. synthesis of carbamoyl phosphate (in mitochondria)

Carbamoyl phosphate synthet

aseⅠ(CPSⅠ)

（ N-acetylglutamate ， Mg2+

）

CO2 + NH3 + H2O + 2ATP

C

O

H2N O ~ PO32- + 2ADP + Pi

carbamoyl phosphate

氨基甲酰磷酸

N- 乙酰谷氨酸

Process of urea cycleProcess of urea cycle

2. Formation of citrulline (in mitochondria)

Ornithine carbamoyl- transferase (OCT)

H3PO4

+

Carbamoyl phosphate

NH2

(CH2)3

CH

COOH

NH2

鸟氨酸

NH2

(CH2)3

CH

COOH

NH2

鸟氨酸

NH2

C

O

O

~PO32-

NH2

C

O

O

~PO32-

NH

CH

COOH

NH2

NH2

C O

瓜氨酸

(CH2)3

Ornithine Citrulline

瓜氨酸

鸟氨酸

NH

CH

COOH

NH2

NH2

C O

瓜氨酸

(CH2)3

Process of urea cycleProcess of urea cycle

3. Synthesis of Arginine (in cytosol)

argininosuccinate synthesase (ASS)

ATP AMP+PPiH2O

Mg2+

+

Aspartate

COOH

C HH2N

CH2

COOH

Citrulline argininosuccinate

NH

(CH2)3

CH

COOH

NH2

NH2

C N

COOH

C H

CH2

COOH

天冬氨酸精氨酸代琥珀酸

Process of urea cycleProcess of urea cycle

Arginine Fumarate

精氨酸代琥珀酸裂解酶

COOH

CH

CH

HOOC

+

NH

(CH2)3

CH

COOH

NH2

NH2

C NH

NH

(CH2)3

CH

COOH

NH2

NH2

C N

COOH

C H

CH2

COOH

NH

(CH2)3

CH

COOH

NH2

NH2

C N

COOH

C H

CH2

COOH

argininosuccinate

Argininosuccin-ate lyase (AST)

3. Synthesis of Arginine

Amino acid

oxaloacetate

Malate

α-ketoglutarate

glutamate

α-ketoacidFumarate

Arginine

Aspartate

argininosuccinate

Reutilization of aspartate

citrulline

Process of urea cycleProcess of urea cycle

4. Hydrolysis of arginine to release urea

Urea ornithineArginine

Arginase

+ NO+ O2

COOH

C HNH2

(CH2)3

NH

C NH

NH2

NADPH+H+ NADP+

COOH

C HNH2

(CH2)3

NH

C O

NH2

Nitric oxide synthase（ NOS ）

Arginine Citrulline

Nitric oxide is the muscle relaxant and gas signal molecule.

Formation fo Formation fo NONO

Summary of Ornithine cycleSummary of Ornithine cycle

NH3

P

• Urea synthesized will be excreted by kidney, some of the urea will enter the intestine and are degraded to ammonia by bacteria.

• To the two nitrogen atoms of urea, one come from ammonia, which come from the degradation of amino acid,

the other one come from Aspartate, which can get the amino group again from other amino acid. So two nitrogen all come from amino acid.

Regulation in urea Regulation in urea biosynthesisbiosynthesis

• Dietary nitrogen intake: high protein diet : synthesis starvation: synthesis

• CPS-Ⅰ: activated by N-acetylglutamic acid (AGA) and arginine

COOH

CH3C-NH-CH

(CH2)2

COOH

O

COOH

CH3C-NH-CH

(CH2)2

COOH

O

N-acetylglutamate

酶 相对活性

氨基甲酰磷酸合成酶

鸟氨酸氨基甲酰转移酶

精氨酸代琥珀酸合成酶

精氨酸代琥珀酸裂解酶

精氨酸酶

4.5

163.0

1.0

3.3

149.0

正常成人肝尿素合成酶的相对活性

酶 相对活性

氨基甲酰磷酸合成酶

鸟氨酸氨基甲酰转移酶

精氨酸代琥珀酸合成酶

精氨酸代琥珀酸裂解酶

精氨酸酶

4.5

163.0

1.0

3.3

149.0

正常成人肝尿素合成酶的相对活性

enzymes

Ornithine transcabamoylase

Relative activity

Argininosuccinate synthetase

arginase

Argininosuccinase

Carbamoyl phosphate synthetase Ⅰ

The relative activity of enzymes of urea cycle in liver

•Key enzyme: Argininosuccinate synthetase

Enzymes in urea cycle

精氨酸代琥珀酸合成酶

HyperammonemiaHyperammonemia 高氨血症高氨血症

• High level of ammonia in the blood.• Reasons: -inborn errors of enzymes in urea

cycle, - liver failure• Damage: (ammonia poisoning) coma and irreversible brain damage

TAC ↓

α-ketoglutarate Glutamate glutamine

NH3NH3

Quantity of α-ketoglutarate in brain↓

Mechanism of the brain damage:

ATP deficiency

Other metabolic Other metabolic pathway of ammoniapathway of ammonia

• Excretion in urine as NH4+ (in kidney)

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

L-glutamate

+ NH3

Glutami-nase

H+

NH4+

NH4+ is excreted in the urine, which can

maintain the acid-base balance of the body.

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH1NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

glutamine ammonium

Other metabolic Other metabolic pathway of ammoniapathway of ammonia

• Synthesis of amino acids non-essential amino acids• Biosynthesis of Pyrimidine 嘧啶

CO2 + glutamine+ H2O + 2ATP

C

O

H2N O ~ PO32- + 2ADP + Pi

carbamoyl phosphate

Carbamoyl phosphate syn

thetase (CPS )Ⅱ Ⅱ

Pyrimidine

Metabolism of the Metabolism of the Carbon Skeleton of Carbon Skeleton of Amino acidsAmino acids

Amino acid

Carbon skeletons

glucose

FA and ketone bodies

TCA

NH3

Urea, uric acid, AA etc

CO2 , H2O and ATP

Pyruvate-ketoglutaratesuccinyl CoAfumarateoxaloacetateacetyl CoAacetoacetyl CoA

AAs

Metabolism of the Metabolism of the Carbon Skeleton of Carbon Skeleton of Amino acidsAmino acids

• Ketogenic amino acids can be degraded to acetyl CoA or acetoacetyl CoA , which are precursor of producing ketone bodies.

Leu, Lys• Glucogenic amino acids can be degraded to

the carbon skeletons which can be converted into glucose.

• Ketogenic and glucogenic amino acids Ile, Phe, Trp, Tyr, Thr

生糖氨基酸

生酮氨基酸

PEP

phosphoglycetate

glucoseglucose

Ala CysGlyThrTrp

Acetyl CoA

pyruvate

IleLeu Trp

AsnAsp

PheTyr Val Thr Met Ile

Leu Lys IleTrp Phe Tyr

Glu

Gln Arg Pro

Acetoacetyl CoA

Keto body

Glycerol 3-phosphate

FAs

Lipids TAG

Succinyl CoA

Fumarate

oxaloacetate

α-ketoglutarate

Citrate

CO2

CO2

T A C

Amino Acid Amino Acid Catabolism: Catabolism: IndividualIndividual

• Decarboxylation of Amino Acid

decarboxylase

Amino Acid Amine

RCH2NH2+ CO2

Puridoxal phosphate

C

COOH

NH2H

R

Physiological effects

• γ-Aminobutyric Acid (GABA) γ- 氨基丁酸 GABA is inhibitory neurotransmitter.

1

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

L-glutamate

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH

GABA

L-glutamate decarboxylase

• Histamine vasodilation 血管舒张

stimulate the secretion of pepsin and hydrochloric acid

Bronchial asthma, allergic reaction

1

Histamine

Histidine decarboxylase

支气管哮喘， 过敏反应

• 5-Hydroxytryptamine (5-HT) 5- 羟色胺 inhibitory neurotransmitter in brain cause contraction （收缩） of smooth mu

scle of arterioles and bronchiolesNH2

CH

(CH2)2

COOH

COOH

NH2

CH

(CH2)2

COOH

COOH1

Tryptophan 5-Hydroxytryptamine

• Polyamine （多胺）： important to cell proliferation （增殖） and tissue growth.

Ornithine Putrescine

S-adenosylmethionine (SAM )

Decarboxylased SAM

Ornithine decarboxylase

CO2

CO2

spermidine

Methythio-adenosine

spermine

腐胺

精脒 精胺

鸟氨酸脱羧酶

Metabolism of One Carbon Metabolism of One Carbon UnitsUnits （（一碳单位）一碳单位）

• One Carbon Units : One carbon containing groups produced in catabolism of some amino acids.

methyl -CH3

methylene -CH2-

methenyl -CH=

formyl -CHO

formimino -CH=NH

甲基

甲烯基

甲炔基

甲酰基

亚胺甲基

Tetrahydrofolate(FH4)

Carrier of one carbon unit: tetrahydrofolate (FH4)

Folic acid FH2 FH4

Dihydrofolate reductase

NADPH+H+ NADP+ NADPH+H+ NADP+

Dihydrofolate reductase

四氢叶酸

N5, N10 nitrogen atoms involved in the transfer of one carbon units.

N5—Methyl —FH4

N5 、 N10—Methylene —FH4

N5 、 N10-Methenyl—FH4

N10—Formyl—FH4

N5—Formimino—FH4

Production of one Production of one carbon unitcarbon unit

Glycine N5, N10—CH2—FH4

N5 、 N10—Methylene —FH4

Serine N5, N10—CH2—FH4

N5 、 N10—Methylene —FH4

Histidine N5—CH=NH—FH4

N5—Formimino—FH4 N5 、 N10-Methenyl—FH

4

N5 、 N10=CH—FH4

Tryptophan N10—CHO—FH4

N10—Formyl—FH4

Conversion of one Conversion of one carbon unitscarbon units

N10—CHO—FH4

N5, N10=CH—FH4

N5, N10—CH2—FH4

N5—CH3—FH4

N5—CH=NH—FH4

H+

H2O

NADPH+H+

NADP+

NADH+H+

NAD+

NH3

Function of one carbon Function of one carbon unitsunits

N10—Formyl—FH4 C2 atom of purine

N5 、 N10-Methenyl—FH

4

C8 atom of purine

N5 、 N10—Methylene —FH

4

Methyl group of thymine

As donors of one carbon units in purine and pyrimidine synthesis.

Metabolism of Methionine, Metabolism of Methionine, Cysteine and CystineCysteine and Cystine

CH2SH

CHNH2

COOH

CH2SH

CHNH2

COOH

Cystine Methionine

sulfur-containing amino acids

CH2

CHNH2

COOH

CH2

CHNH2

COOH

S SCH2

CHNH2

COOH

CH2

CHNH2

COOH

S S S CH3

CH2

CHNH2

COOH

CH2

S CH3

CH2

CHNH2

COOH

CH2

Cysteine

Homocysteine methyltransferase (Vitamine B12)

Macrocytic anemia

Methionine cycleMethionine cycle

SAM

同型半胱氨酸代谢紊乱同型半胱氨酸代谢紊乱

• 血浆总 HCY 水平正常范围： 5-15μmol/L ，

同型半胱氨酸

甲硫氨酸维生素 B6 半胱氨酸

叶酸、维生素 B12 甲硫氨酸

胱硫醚 -β- 合成酶（ CBS ）

N5N10- 亚甲基四氢叶酸还原酶 (MTHFR)

甲硫氨酸合成酶（ MS ）

高高 HCYHCY 血症原因 血症原因

• 遗传性代谢障碍：酶基因缺陷 MTHFR 、 MS 、 CBS 基因突变• 获得性代谢障碍： 摄入的 B6 、 B12 、叶酸等维生素不足

同型半胱氨酸与动脉粥样硬化同型半胱氨酸与动脉粥样硬化

• 高同型半胱氨酸血症是动脉硬化和冠心病的一个独立危险因素

作用机制

自身氧化作用

形成内酯化合物 血小板凝集

血凝块的形成粥样硬化斑块加速

内皮损伤

缺氧

• 目前血浆 HCY 检测可作为心脑血管病临床常规检查指标。

血脂正常，胆固醇不高的人群有严重 AS 性疾病和家族史人群有早期 ( ＜ 50 岁 ) 冠心病、脑血管或外周

血管病症状的人群服用氨甲喋呤、氨茶碱、苯妥英等人群中，

HCY 升高的比例较高，有进一步引发血管疾病的可能，需要联合考虑。

HCY 检测适应症

Creatinine

Creatine and creatine phosphateCreatine and creatine phosphate

Arginine +

Glycine

transamidinase

ornithine Guanidoacetate

S-adenosyl- homocysteine

1

Creatine

Creatine kinase

Creatine phosphate

H2O

Storage of ‘high

energy’ phosphate

of ATP

Cysteine and CystineCysteine and Cystine

• Conversion of cysteine to cystine

-2H

+2H

CH2SH

CHNH2

COOH

CH2

CHNH2

COOH

CH2

CHNH2

COOH

S S

2

Cysteine Cystine

•Systhesis of Taurine （牛磺酸）

CH2SH

CHNH2

COOH

CH2SO3H

CHNH2

COOH

CH2SO3H

CH2NH2

Cysteine Cysteine sulfate

Taurine

CO2

1.Form conjugant with bile acid.2.Involved in brain development

Formation of Formation of PAPSPAPS

SO42- + ATP AMP - SO3

- (adenosine -5´-phosphosulfate)

3-PO3H2-AMP-SO3-

（ 3´-phosphoadenosine-5´-phosphosulfate ， PAPS）

Sulfate is produced mostly from cysteine.

PAPSPAPS is the active sulfate group for biosynthesis.

A

3´- 磷酸腺苷 -5´- 磷酸硫酸

Glutathione (GSH)Glutathione (GSH)

• transport amino acids across membranes.• Protect erythrocytes （红血球） from oxid

ative damage.

γ-glutamylcysteinylglycine

CHH2N

COOH

R

Amino acid

cysteineglycine

(Cys-Gly)

GSH

1

γ-glutamyl-amino acid

COOH

CHNH2

CH2

CH2

C

O

NH CH

COOH

R

γ-glutamyl-transpeptidase

Amino acid

H2NCH

COOH

R

5-Oxiproline

Glutamate

ATP

ADP+Pi

γ-glutamylcysteine ADP+Pi

ATP

ATPADP+Pi

γ-glutamyl cycle Cell membrane

Metabolism of Metabolism of aromatic amino acidsaromatic amino acidsaromatic amino acidsaromatic amino acids

phenylalanine Tyrosine Tryptophan

Phenylalanine and Phenylalanine and Tyrosine Tyrosine

phenylalanineTyrosine

Phenylalanine hydroxylase

O2 H2O

The main catabolism pathway of phenylalanine is hydroxylated to tyrosine first.

Phenylketonuria (PKU)• Normally, small amount of phenylalanine can

be transaminated to form phenylpyruvate. 苯丙酮酸

• If phenylalanine hydroxylase is genetic deficiency, transamination become the main catabolism pathway, which results in high level of phenylpyruvate and phenyllacetate in the urine, called phenylketonuria （ PKU ）

苯酮酸尿症

phenylpyruvate phenyllacetatephenylalanine

transamination

p

苯丙酮酸 苯乙酸

• 病因：遗传性苯丙氨酸羟化酶缺陷，苯丙氨酸不能正常转变为酪氨酸，可经转氨基作用生成苯丙酮酸、苯乙酸等，并从尿中排出

• 临床表现：智力缺陷 , 毛发和皮肤较正常人略浅，身体有霉臭味，尿有鼠尿样气味，易流口水及出汗，有反复发作的惊厥、肌张力高，躯体前后摇摆，行动困难。

• 治疗：低苯丙氨酸膳食

• PKU 的早期诊断十分必要。•新生儿 PKU 筛查的常用方法： Guthrie试验、荧光光度法、苯丙氨酸脱氢酶法。

•新生儿的筛查在欧美国家广泛地进行。•新生儿 PKU 的诊断试验：色谱法、荧光分光光度法、 FeCl3法检测尿中苯丙酮酸。

• 用 PCR-ASO探针法和 PCR-RFLP连锁分析法可鉴定出导致 PKU 的点突变。

Metabolism of Metabolism of tyrosinetyrosine

• Production of Dopamine, Epinephrine and Norepinephrine.

Tyrosine Dopamine 多巴胺

Epinephrine 肾上腺素 Norepinephrine

Dopa 多巴

Tyrosine hydroxylase

SAM

Parkinson’s disease

Reasons:

• deficiency of Dopamine

slowing of emotional and voluntary movement, muscular rigidity, postural abnormality and tremor

character :

Metabolism of Metabolism of tyrosinetyrosine

• Synthesis of Melanin Tyrosine Dopa Melanin• Genetic lack of tyrosinase （酪氨酸酶） will

cause Albinism （白化病） . --lack of pigment in the skin and eyes. --sensitive to sunlight --photophobia

tyrosinase

• Production of thyroid Hormone

thyroxine (T4) and triiodothyronine (T3)甲状腺素 三碘甲状腺氨酸

Metabolism of tryptophan Metabolism of tryptophan

tryptophantryptophan

5-hydroxytryptamine

One carbon units

pyruvate + acetoacetyl CoA

Nicotinic acid 尼克酸

Melatonin 褪黑激素

Degradation of Degradation of branched-chain amino branched-chain amino acidacid

CH3

CH

CH2

CHNH2

COOH

CH3

CH3

CH

CH2

CHNH2

COOH

CH3CH3

CH

CHNH2

COOH

CH3

CH3

CH

CHNH2

COOH

CH3

CH3

CH

CH2

CHNH2

COOH

CH3

CH3

CH

CH2

CHNH2

COOH

CH3

leucine isoleucine valine

branched-chain amino acidbranched-chain amino acid

Succinyl CoA

Acetyl CoA+

Acetoacetate

Succinyl CoA

+Acetyl CoA