A i Aid MtbliAmino Acids Metabolismosp.mans.edu.eg/medbiochem_mi/Cources/Biochemistry/... · Creatine and creatinrne synthesis 6. Sthi fltthiSynthesis of glutathione 7. Haeme biosynthesis

A i A id M t b liA i A id M t b liAmino Acids MetabolismAmino Acids Metabolism

Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi

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Gl i M t b liGl i M t b liGl i M t b liGl i M t b li••Glycine MetabolismGlycine Metabolism••Glycine MetabolismGlycine Metabolism


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GlycineGlycineGlycineGlycineNH2

CH COOH• It is α-amino acetic acid

StructureStructure CH2 COOH

Nutrional ValueNutrional Value• It is non-essential amino acid

Metabolic FateMetabolic Fate• It is glucogenic amino acid

Metabolic FateMetabolic Fateg g


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GlycineGlycineGlycineGlycine

BiosynthesisBiosynthesis

1. From CO2 and NH3


2 3

2. From glyoxylic acid 3 F i3. From serine4. From threonine 5. From choline6 F h d li6. From hydroxy proline


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GlycineGlycine11-- Biosynthesis from COBiosynthesis from CO22 and NHand NH33

N5 N10 methylene H f l

CO + NHNH2

N5, N10 methyleneH4 folate

H4 folate

CO2 + NH3 CH2 COOH

GlycineGlycine synthetaseGlycine synthetase

NADH H+ NAD+ GlycineNADH.H NAD


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GlycineGlycine22-- Biosynthesis from glyoxylic acidBiosynthesis from glyoxylic acid

k l i

NH2

Glutamic acid α ketoglutaric

OPLP

CH2 COOH

GlycineAminotransferaseAminotransferase

CH COOH

Glyoxylic

PLP

GlycineGlyoxylic


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33-- Biosynthesis from serineBiosynthesis from serine33 Biosynthesis from serineBiosynthesis from serine

th lmethyleneH4 FolateH4 Folate

NH2OH NH2

CH2 COOHSerine hydroxymethylSerine hydroxymethyl

transferasetransferase Glycine

CH2 CH COOH

S i GlycineSerine


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44-- Biosynthesis from threonineBiosynthesis from threonine44 Biosynthesis from threonineBiosynthesis from threonine

NH2 ONH2OH

CH2 COOHThreonie aldolaseThreonie aldolase

GlycineTh i

CH3 CH+CH3 CH CH COOH

AcetaldehydeGlycineThreonine Acetaldehyde


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GlycineGlycine55-- Biosynthesis from cholineBiosynthesis from choline

CH3O CH3

CH3

N3

CH3

CH3

CH2 C H

Betaine aldehyde

N3

CH3

CH3

CH2 COOH

Betaine

NCH3

CH3

CH2 CH2 OH

CholineCholine 2H

O

Betaine aldehyde Betaine2H

ii CH3

CHCH2O CH2O

serineserine

NCH3

CH

CH2 COOHNH2

CH2 COOH NHCH3 CH2 COOH

CH2O

CH3 Dimethyl glycinemonomethyl glycine(sarcosine)

GlycineGlycine


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GlycineGlycine66 Biosynthesis from hydroxy prolineBiosynthesis from hydroxy proline66-- Biosynthesis from hydroxy prolineBiosynthesis from hydroxy proline

HO OH HC OHC

COOH

OH

NH

COOHHO

CH CH2 CH COOH

NH2HC

OHC

CH2

HC OH

HC

CH2

HC

NH2

OHoxidationoxidation

COOH

HC NH2γ hydroxy glutamic γ semialdehyde

COOHγ hydroxy glutamic

Hydroxy proline

COOH

transamination

C

CH2

HC

O

OHO

C COOHCH3

O

CH COOH

NH2

CH2 COOH + Aldolasetransamination

COOH

C O

γ hydroxy α ketoglutamicPyruvic acidGlyoxylicGlycine


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1.1. From COFrom CO22 and NHand NH33


22 33

2.2. From glyoxylic acid From glyoxylic acid 33 F iF i3.3. From serineFrom serine4.4. From threonine From threonine 5.5. From cholineFrom choline66 F h d liF h d li6.6. From hydroxy prolineFrom hydroxy proline


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GlycineGlycineMetabolic FateMetabolic Fate

1. Cleavage to CO2 and NH32 F ti f l li id

Metabolic FateMetabolic Fate

2. Formation of glyoxylic acid 3. Biosynthesis of serine4 S th i f l4. Synthesis of glucose5. Creatine and creatinrne synthesis 6 S th i f l t thi6. Synthesis of glutathione7. Haeme biosynthesis8 S th i f i b8. Synthesis of purine bases 9. Detoxication of benzoic acid10 C j ti ith bil id10. Conjugation with bile acids11. Incorporated in tissue proteins


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GlycineGlycine11-- Cleavage into COCleavage into CO22 and NHand NH33

N5 N10 methylene

CO NHNH2

CH COOH

N5, N10 methyleneH4 folateH4 folate

CO2 + NH3CH2 COOH


NADH H+NAD+y NADH.H


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GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid

GlycineGlycine

NH2Glutamic acidα ketoglutaric

O

CH COOHPLPCH2 COOH


CH COOH

Glyoxylic

FormicFormic


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33-- Biosynthesis of serineBiosynthesis of serine33 Biosynthesis of serineBiosynthesis of serine

methyleneH4 Folate

H4 Folate

NH2 OH NH22

CH2 COOHSerine hydroxymethylSerine hydroxymethyl

transferasetransferaseGlycine

CH2 CH COOH

S iGlycine Serine


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44-- Glucose synthesisGlucose synthesis44 Glucose synthesisGlucose synthesis

dehydratsedehydratsePyruvic acidGlycine Serine

Serine hydroxymethylSerine hydroxymethyl

dehydratsedehydratse

transferasetransferase

Glucose


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GlycineGlycineGlycineGlycine55-- Biosynthesis of Creatine and creatinrneBiosynthesis of Creatine and creatinrne

NH2HN NH2HN

Transamidinase NH2NH2

CH2

CH

NH2

CH2

CH

NH2

CH2

NHC

CH2

NHC

+H2N CH2 COOHTransamidinase

+ HNC

NH2HN

CH2 COOHHNC

NH2HN

CH2 COOH

CH2

CH2

HC NH2

CH2

CH2

HC NH2

CH2

CH2

CH2

CH2

Glycine OrnithineGuanidoacetic

Arginine

COOH2

COOH2HC

COOH

NH2HC

COOH

NH2

Glycine Ornithine acidArginine


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Biosynthesis of Creatine and creatinineBiosynthesis of Creatine and creatinineNH NH2

NHCH2

CHNNH2

NH2

CH2

CH2CH2

Guanidoacetic acid

Ornithine

CH2

CH2CH2

HC NH2

H2N CH2 COOHHN CH2 COOH

CHNNH2

CH2HC

COOHNH2

A i i Gl i

acid

+KidneyKidney

HCCOOH

NH2 HN CH2 COOHArginine GlycineTransamidinase

S-Adenosyl methionine

GlycineArginine Glycine

Guanidoacetate methyltransferase

NH2NH PCHNNH C O

S-Adenosyl homocysteineCreatine phosphate

LiverLiver

MuscleMuscle

N CH2 COOH

CHN

CH3

N CH2 COOH

CHN

CH3Pi +H2O

N CH2

CH3CreatineCreatinine ATPADP

Creatine Kinase


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3Creatinine

Blood levelCreatine and CreatinineCreatine and Creatinine

Creatine 0.2-0.6 mg/dl.Creatinine 0.5-1.2 mg/dl

Urinary excretionNormally creatine is present in very small amount in urine.Normal urine creatinine levels: 1 – 2 g/24 hours Creatinine excretion for each individual is constant

Creatinine coefficientMales: 20 – 30 mg/kg/24 hoursFemales: 10 – 20 mg/kg/ 24 hours

Creatinine ClearanceMales: 90 - 130 ml/minuteFemales: 80 – 120 ml/minute


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CreatinuriaCreatinuriaPhysiological causes

In childrenIn females: during pregnancy and after labour In females: during pregnancy and after labour Prolonged administration of androgens

Pathological causesgDegenerative Muscular dystrophy.

Myasthenia gravis. l lAcute poliomyelitis.

HypogonadismIncrease tissue catabolismIncrease tissue catabolism

Hyperthyroidism Starvation Diabetes mellitus Tumors


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GlycineGlycine77 Bi th i f l t thiBi th i f l t thi77-- Biosynthesis of glutathioneBiosynthesis of glutathione

CH COOHNHCO

COOH CH COOHNH

CH2

NH2γ Glutamyl cysteinesynthetase

γ Glutamyl cysteine

H2OCH COOHNHCH2

SH

CCH2

CH2HC NH

COOHCH2

CH2HC NH2 C t i

CH COOHNH2

CH2

SH+

COOHADP+Pi GlycineATP

γ Glutamyl cysteineHCCOOH

NH2HCCOOH

NH2

Glutamic acid

Cysteine

CH CNHCO

NHO

ATP

CH CNHCH2

SH

CCH2

CH2HC NH2

CH2

COOH

NHADP+Pi

H2OCOOH

2

(γ Glutamyl cysteinyl glycine)Glutathione

2


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l h d ll f h l b

Functions of glutathioneFunctions of glutathioneGlutathione protects red cells from haemolysis by H2O2

It protects haemoglobin against oxidation by H2O2p g g y 2 2

Glutatione has a role in an amino acid transport system

It inactivates insulin in the liver.

It maintains (-SH) group which is important for the activity of It maintains (-SH) group, which is important for the activity of

many enzymes.

It protects the B-cells of pancreas from the degenerative action

f llof alloxan

Glutathione acts as a hydrogen carrier


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y

2 G SHGlutathione peroxidase

G S S G 2 H OH2O2 + 2 G-SH G-S-S-G 2 H2O

Glutathione reducase

+Selenium

NADPH+H+NADP

7 20

SS

SS

SH SH

SH SH

7 20α chain 21 aa

Insulin GlutathioneT h d

7 19β chain 30 aa

Insulin 4 G-SHTranshydrogenase

2 G-S-S-G 2 separate peptides++


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GlycineGlycine77-- Biosynthesis of HaemeBiosynthesis of Haeme77-- Biosynthesis of HaemeBiosynthesis of Haeme

COOHCH2

COOHCH

COOHCH2l C

oA

2

CH2CS

OCoA

CH2

CH2C O

CH2

CH2

C OALA synthetase ALA synthetase

PLP

Succ

inyl

+ CoASH HC

COOHNH2 H2C NH2CO2

PLP

Gly

cine

α amino β ketoadepic acid δ aminolevulinic acidHC

COOHNH2

H

COOHCOOHCH2

COOHCH2

COOHCH2

CH

COOH

CH2

CH2

CH2

CO2 H O

ALA dehydrataseCH2

C

C

CH2

C

C HC O

CH2

NH2

C

NHH

HH2 H2O C

CH2

NH2

C

NH

H

Porphobilinogen


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GlycineGlycine88 Bi th i f i bBi th i f i b88-- Biosynthesis of purine basesBiosynthesis of purine bases

NH2

N CC N

1 56 7

HCN

C NCH2

34

89

N NH


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GlycineGlycine99 Detoxication by conjugationDetoxication by conjugation99-- Detoxication by conjugationDetoxication by conjugation

CoA SH

COOH

CoA.SH

CO

S.CoA

Benzoic acid Benzoyl CoAATP ADP+Pi

OO

Benzoyl CoA

C S.CoA

+NH2

CH2 COOHCoA.SH C

ONHCH2 COOH

Glycine Hippuric acid


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GlycineGlycine1010 C j ti ith bil idC j ti ith bil id1010 –– Conjugation with bile acidsConjugation with bile acids

OH OHCOOH

HO OH

C

HO OH

OS.CoA NH2

CH2 COOH COH

ONHCH2 COOH

+HO H

OH HO HOH

CoA.SHHO H OH

Cholic AcidCholyl CoA

Glycocoholic Acidy

KNa

Ch n d x h li A id Ch d h l l C A

K glycocoholateNa glycocoholate

Chenodeoxycholic Acid Chenodeoxyholyl CoA Glycochenodeoxycoholic Acid


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GlycineGlycineGlycineGlycineCatabolic FateCatabolic Fate

1.1. Cleavage to COCleavage to CO22 and NHand NH33

2.2. Formation of glyoxylic acid Formation of glyoxylic acid 33 Glycine threonine cycleGlycine threonine cycle3.3. Glycine threonine cycleGlycine threonine cycle4.4. Glycine succinate cycleGlycine succinate cycle


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GlycineGlycine11-- Cleavage into COCleavage into CO22 and NHand NH33

N5 N10 methylene

CO NHNH2

CH COOH

N5, N10 methyleneH4 folateH4 folate

CO2 + NH3CH2 COOH


NADH H+NAD+y NADH.H


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GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid

GlycineGlycine

NH2Glutamic acidα ketoglutaric

O

CH COOHPLPCH2 COOH


CH COOH

Glyoxylic

FormicFormic


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NH2OHO

33-- Glycine threonine cycleGlycine threonine cycleCH3 CH CH COOH

2

NH

CH3 CH

ThreonineAcetaldehyde

CH2 COOHNH2

CH3 C CH COOHNH2

OCH3 COOH

α Amino βGlycineAcetic acid

CoA.SH

CO

CH3 CO

S.CoA CH3 C CH2

O

NH2

βketobutyric

A i iA l C A

CO2

CO2

NH3

AminoacitoneAcetyl CoA

CH3 C CHO

OCH3 C COOH

OPyruvic acid

Glyoxal

CH3 CH COOHOH

-2HLactic acid


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COOHCH2CHse ALA

44-- Glycine succinate cycleGlycine succinate cycle

COOHCH2CH2

CH2C O

HC

COOHNH2

ALA synthetase

CoASHPLPCOOHCH2

CH2

ALA synthetase

CO2HaemeCH2

CS

OCoA

HC NH2Succinyl CoA

α amino β ketoadepic acid

H

C O

H2C NH2δ aminolevulinic acid

Haeme

H O COOHGlycine

COOHCH2

GDP+Pi

H2O

Succinate thiokinase

COOHCH2COOH

NH3

OxidationCH2

C O

COOH

GTP

CoA.SH

CO CH2

C O

CH

CH2

CH2

COOH COOHCH2 OS i i id

Oxida

α Ketoglutaric acidCO2

α Ketoglutaraldehyde

2

CH2

C O

H

OSuccinic acid idation


٣٢Succinic semialdehyde

GlycineGlycineyyInborn errors of glycine metabolismInborn errors of glycine metabolism

1 Primary hyperoxaluria1. Primary hyperoxaluria

2 Glycinuria2. Glycinuria


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GlycineGlycineI b f l i t b liI b f l i t b li

1. Primary hyperoxaluriaInborn errors of glycine metabolismInborn errors of glycine metabolism

Failure to metabolize glyoxylic acid normally


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NHSources and fate of glyoxylic acidSources and fate of glyoxylic acid

NH2

CH2 COOHGlycine

Glyciney

O

CH COOH

H-COOHFormic acid

CH COOHGlyoxylic COOH

COOH

H d x p lin

Oxalic acid

Hydroxy proline

UrineUrine


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GlycineGlycineI b f l i t b liI b f l i t b li

1. Primary hyperoxaluriaInborn errors of glycine metabolismInborn errors of glycine metabolism

Failure to catabolize glyoxylic acid normallySubsequent oxidation of glyoxylic to oxalic acid q g y yIncreased excretion of oxalic acid in urine in the

form of calcium oxalate•This results in:

•Urolithiasis•Nephrocalcinosis•Early mortality fromy y

•Renal failure •Hypertension.


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yp

GlycineGlycine

2 Gl i i

Inborn errors of glycine metabolismInborn errors of glycine metabolism2. Glycinuria

Excess excretion of glycine in urineExcess excretion of glycine in urine

Glycine level in blood is normal y

A defect in renal tubular reabsorption of glycine

Oxalate excretion in urine is normal.

T d f f ti f l t i t Tendency of formation of oxalate urinary stones


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II

ABB

• A


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II

ABB

• A


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A i Aid MtbliAmino Acids Metabolismosp.mans.edu.eg/medbiochem_mi/Cources/Biochemistry/... · Creatine and creatinrne synthesis 6. Sthi fltthiSynthesis of glutathione 7. Haeme biosynthesis

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