a i aid mtbliamino acids metabolismosp.mans.edu.eg/medbiochem_mi/cources/biochemistry/... ·...

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

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

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

GlycineGlycineGlycineGlycine

BiosynthesisBiosynthesis

1. From CO2 and NH3

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

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

GlycineGlycine22-- Biosynthesis from glyoxylic acidBiosynthesis from glyoxylic acid

Glutamic acid α ketoglutaric

CH2 COOH

GlycineAminotransferaseAminotransferase

CH COOH

Glyoxylic

GlycineGlyoxylic

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

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

GlycineGlycine55-- Biosynthesis from cholineBiosynthesis from choline

CH3O CH3

CH2 C H

Betaine aldehyde

CH2 COOH

Betaine

CH2 CH2 OH

CholineCholine 2H

Betaine aldehyde Betaine2H

ii CH3

CHCH2O CH2O

serineserine

CH2 COOHNH2

CH2 COOH NHCH3 CH2 COOH

CH3 Dimethyl glycinemonomethyl glycine(sarcosine)

GlycineGlycine

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

HO OH HC OHC

COOHHO

CH CH2 CH COOH

OHoxidationoxidation

HC NH2γ hydroxy glutamic γ semialdehyde

COOHγ hydroxy glutamic

Hydroxy proline

transamination

C COOHCH3

CH COOH

CH2 COOH + Aldolasetransamination

γ hydroxy α ketoglutamicPyruvic acidGlyoxylicGlycine

1.1. From COFrom CO22 and NHand NH33

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

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

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

GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid

GlycineGlycine

NH2Glutamic acidα ketoglutaric

CH COOHPLPCH2 COOH

CH COOH

Glyoxylic

FormicFormic

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

44-- Glucose synthesisGlucose synthesis44 Glucose synthesisGlucose synthesis

dehydratsedehydratsePyruvic acidGlycine Serine

Serine hydroxymethylSerine hydroxymethyl

dehydratsedehydratse

transferasetransferase

Glucose

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

NH2HN NH2HN

Transamidinase NH2NH2

+H2N CH2 COOHTransamidinase

CH2 COOHHNC

CH2 COOH

HC NH2

Glycine OrnithineGuanidoacetic

Arginine

COOH2HC

Glycine Ornithine acidArginine

Biosynthesis of Creatine and creatinineBiosynthesis of Creatine and creatinineNH NH2

CHNNH2

CH2CH2

Guanidoacetic acid

Ornithine

CH2CH2

HC NH2

H2N CH2 COOHHN CH2 COOH

CHNNH2

COOHNH2

A i i Gl i

+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

CH3Pi +H2O

CH3CreatineCreatinine ATPADP

Creatine Kinase

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

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

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

CH COOHNHCO

COOH CH COOHNH

NH2γ Glutamyl cysteinesynthetase

γ Glutamyl cysteine

H2OCH COOHNHCH2

CH2HC NH

COOHCH2

CH2HC NH2 C t i

CH COOHNH2

COOHADP+Pi GlycineATP

γ Glutamyl cysteineHCCOOH

NH2HCCOOH

Glutamic acid

Cysteine

CH CNHCO

CH CNHCH2

CH2HC NH2

NHADP+Pi

H2OCOOH

(γ Glutamyl cysteinyl glycine)Glutathione

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

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 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++

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

COOHCH2

COOHCH

COOHCH2l C

CH2C O

C OALA synthetase ALA synthetase

+ CoASH HC

COOHNH2 H2C NH2CO2

α amino β ketoadepic acid δ aminolevulinic acidHC

COOHNH2

COOHCOOHCH2

COOHCH2

CO2 H O

ALA dehydrataseCH2

C HC O

HH2 H2O C

Porphobilinogen

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

N CC N

1 56 7

C NCH2

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

CoA SH

CoA.SH

Benzoic acid Benzoyl CoAATP ADP+Pi

Benzoyl CoA

C S.CoA

CH2 COOHCoA.SH C

ONHCH2 COOH

Glycine Hippuric acid

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

OH OHCOOH

OS.CoA NH2

CH2 COOH COH

ONHCH2 COOH

OH HO HOH

CoA.SHHO H OH

Cholic AcidCholyl CoA

Glycocoholic Acidy

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

K glycocoholateNa glycocoholate

Chenodeoxycholic Acid Chenodeoxyholyl CoA Glycochenodeoxycoholic Acid

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

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

GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid

GlycineGlycine

NH2Glutamic acidα ketoglutaric

CH COOHPLPCH2 COOH

CH COOH

Glyoxylic

FormicFormic

NH2OHO

33-- Glycine threonine cycleGlycine threonine cycleCH3 CH CH COOH

CH3 CH

ThreonineAcetaldehyde

CH2 COOHNH2

CH3 C CH COOHNH2

OCH3 COOH

α Amino βGlycineAcetic acid

CoA.SH

CH3 CO

S.CoA CH3 C CH2

βketobutyric

A i iA l C A

AminoacitoneAcetyl CoA

CH3 C CHO

OCH3 C COOH

OPyruvic acid

Glyoxal

CH3 CH COOHOH

-2HLactic acid

COOHCH2CHse ALA

44-- Glycine succinate cycleGlycine succinate cycle

COOHCH2CH2

CH2C O

COOHNH2

ALA synthetase

CoASHPLPCOOHCH2

ALA synthetase

CO2HaemeCH2

HC NH2Succinyl CoA

α amino β ketoadepic acid

H2C NH2δ aminolevulinic acid

H O COOHGlycine

COOHCH2

GDP+Pi

Succinate thiokinase

COOHCH2COOH

OxidationCH2

CoA.SH

CO CH2

COOH COOHCH2 OS i i id

α Ketoglutaric acidCO2

α Ketoglutaraldehyde

OSuccinic acid idation

٣٢Succinic semialdehyde

GlycineGlycineyyInborn errors of glycine metabolismInborn errors of glycine metabolism

1 Primary hyperoxaluria1. Primary hyperoxaluria

2 Glycinuria2. Glycinuria

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

NHSources and fate of glyoxylic acidSources and fate of glyoxylic acid

CH2 COOHGlycine

Glyciney

CH COOH

H-COOHFormic acid

CH COOHGlyoxylic COOH

H d x p lin

Oxalic acid

Hydroxy proline

UrineUrine

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.

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

a i aid mtbliamino acids metabolismosp.mans.edu.eg/medbiochem_mi/cources/biochemistry/... ·...

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