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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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GlycineGlycineGlycineGlycine
BiosynthesisBiosynthesis
1. From CO2 and NH3
BiosynthesisBiosynthesis
2 3
2. From glyoxylic acid 3 F i3. From serine4. From threonine 5. From choline6 F h d li6. From hydroxy proline
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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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GlycineGlycineGlycineGlycine
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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GlycineGlycineGlycineGlycine
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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
١٠
GlycineGlycineGlycineGlycine
BiosynthesisBiosynthesis
1.1. From COFrom CO22 and NHand NH33
BiosynthesisBiosynthesis
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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
GlycineGlycine synthetaseGlycine synthetase
NADH H+NAD+y NADH.H
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid
GlycineGlycine
NH2Glutamic acidα ketoglutaric
O
CH COOHPLPCH2 COOH
GlycineAminotransferaseAminotransferase
CH COOH
Glyoxylic
FormicFormic
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GlycineGlycineGlycineGlycine
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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GlycineGlycineGlycineGlycine
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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٢٢
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++
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
GlycineGlycine synthetaseGlycine synthetase
NADH H+NAD+y NADH.H
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٢٩
GlycineGlycine22-- Formation of glyoxylic acidFormation of glyoxylic acid
GlycineGlycine
NH2Glutamic acidα ketoglutaric
O
CH COOHPLPCH2 COOH
GlycineAminotransferaseAminotransferase
CH COOH
Glyoxylic
FormicFormic
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٣٠
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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٢Succinic semialdehyde
GlycineGlycineyyInborn errors of glycine metabolismInborn errors of glycine metabolism
1 Primary hyperoxaluria1. Primary hyperoxaluria
2 Glycinuria2. Glycinuria
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
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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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٤
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
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٥
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.
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٦
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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٣٧
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٨
II
ABB
• A
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٣٩
II
ABB
• A
Prof Dr Mohammad Ibrahim Prof of Medical Biochemistry http://osp.mans.edu.eg/medbiochem_mi
٤٠