Metabolism of Glycine

1. Metabolism of Glycine Dr. Ketki K Assistant Professor Dept of Biochemistry HIMS Varanasi

2. Content • Chemistry • Overview of glycine metabolism • Synthesis of glycine • Degradation of glycine • Specialized products from glycine • Disorders

3. Glycine: Chemistry • Simple amino acid • Non essential amino acid • Metabolically - glucogenic amino acid • Involved in one-carbon metabolism • Present in the interior structure of protein, eg: Collagen,every 3rdaa is glycine • Specialized products synthesized form glycine,eg:heme, purines, creatine etc.

4. Glycine metabolism

5. Synthesis of Glycine Glycine is synthesized : • From Serine • From Threonine • From CO2, NH3 • From Glyoxalate

6. From serine • Glycine is synthesized from serine by the enzyme serine hydroxymethyltransferase which is dependent on tetrahydrofolic acid (THFA). • Beta carbon of serine is removed : enters one carbon pool with help of THFA • Alpha cabron of serine : becomes alpha carbon of glycine

8. From serine Serine hydroxy methyl transferase Serine Glycine THFA N5,N10 methylene THFA

9. From Threonine • Glycine can also be obtained from threonine, catalysed by threonine aldolase Threoninealdolase Threonine Glycine + acetaldehyde

11. From CO2, NH3 • Glycine can be synthesized by the glycine synthase reaction from CO2, NH3 & one carbon unit • Reversal of the glycine cleavage system • Multienzyme complex • Needs co-enzymes NAD, lipoamide, THFA & PLP

12. From CO2, NH3 N5,N10Methylene THFA Glycinesynthase complex, PLP THFA CO2 + NH3 Glycine NADH + H+ NAD+

13. From Glyoxalate • Glycine amino transferase: catalyze the synthesis of glycine from glyoxylate & glutamate or alanine • This reaction strongly favors synthesis of glycine

14. From Glyoxalate pyruvate alanine PLP Glyoxalate Glycine Glycine amino-transferase / alanineglyoxalate amino transferase

16. Degradation of glycine • Glycine : oxidative deaminaion (by reversal of glycinesynthase) : to liberate NH3, CO2 & one carbon unit as methylene THFA • It is a multienzyme complex • It requires co-enzymes -NAD, Lipoamide, THFA, PLP • PLP-dependent glycinedecarboxylase • Lipoamide containing amino methyltransferase • Methylene THFA synthesizing enzyme • NAD+ dependent lipoamidedehydrogenase • Major route for glycine breakdown in mammals

18. GlucogenicPathway • Glycine converted to serine,reversal of serine hydroxy methyltransferase reaction • The serine is then converted to pyruvate by serine dehydratase • Pyruvate serves as a precursor for glucose

20. Synthesis of specialized products from glycine • Creatine,creatine phosphate & creatinine • Heme • Purine nucleotides • Glutathione • Conjugating agent • Neurotransmitter

21. Biosynthesis of creatine • Creatine: present in the muscle tissues as a high energy compound, phosphocreatine & as free creatine • Three amino acids glycine, arginine & methionine: required for creatine formation

23. Steps in biosynthesis of creatine Step-1: • The first reaction occurs in the mitochondria of kidney & pancreas • It involves the transfer of guanidino group of arginine to glycine, catalysed by glycine- arginine amidotransferase to produce guanidoacetate

24. Step-2: • S-Adenosylmethionine (active methionine) donates methyl group to guanidoacetate to produce creatine • This methylation reaction occurs in liver

25. Step-3: • Creatine : reversibly phosphorylated to phosphocreatine (creatine phosphate) by creatine kinase, needs hydrolysis of ATP • phosphocreatine : stored in muscle as high energy phosphate, serves as an immediate store of energy in the muscle

26. During muscle contraction, energy from hydrolysis of ATP • ATP regenerated by hydrolysis of creatine phosphate, c/a Lohmann’s reaction

28. Step-4: • The creatine phosphate: converted to creatinine • Non-enzymatic spontaneous reaction • Creatinine : excreted in urine

30. Normal ranges of creatinine & creatine: • Serum level: Serum creatinine : 0.7 - 1.4 mg/dl Serum creatine : 0.2 - 0.4 mg/dl • Urine level: • Creatinine: 1 - 2 gm/day • Creatine: 0 - 50 mg/day

31. Clinical Applications • Creatinine level in blood sensitive indicator of renal function, Creatinine Clearance – measure of GFR • In muscular dystrophies, blood creatine,creatinine & urinary creatinine are increased • Elevated serum creatinine: in renal failure,fever,starvation • The enzyme CK is elevated in Myocardial infarction

32. Excretion of creatinine: constant for an individual depends on muscle mass • Normally , urine contains – creatine (less) • Creatinuria– increased excretion of creatinein urine : in Muscular dystrophy

33. Synthesis of heme • Glycine condenses with succinyl CoA to form δ-amino levulinic acid • which serves as a precursor for heme synthesis ALA Synthase Glycine + Succinyl CoA Amino levulinate (ALA)

34. Synthesis of purine ring • The entire molecule of glycine is utilized for the formation of positions 4 & 5 of carbon & position 7 of nitrogen of purines ( C4,C5 & N7)

35. Synthesis of glutathione • Tri-peptide, containing glutamic acid, cysteine, glycine • Reduced form (GSH) & Oxidized form (GSSG) • Important in maintaining RBC membrane integrity

36. Glutathione

37. Conjugation reactions • Conjugating agent, glycine performs two important functions • The bile acids: • Cholic acid & chenodeoxy cholic acid- are conjugated with glycine Cholic acid + glycine Glycocholic acid Chenodeoxycholic acid + glycine Glycochenodeoxycholic acid

38. Benzoic acid : used as preservative in food • Benzoic acid is used to detoxify amino nitrogen in the form of glycine = forms benzoyl glycine, water soluble compound, easily excreted BenzoylCoA + glycine Hippuric acid/benzoyl glycine + CoA

39. Glycine as a Neurotransmitter • Glycine : in the brainstem & spinal cord • Glycine opens chloride specific channels • In moderate levels, Glycine inhibits neuronal traffic; but at high levels, it causes over-excitation

40. Glycine as a Constituent of Protein • Glycine: seen where the polypeptide chain bends or turns (beta bends or loops) • In collagen, every 3rd amino acid is glycine

41. Metabolic disorders of glycine • Non-ketotic Hyperglycinemia (NKH): Due to defect in glycine cleavage system Glycine level: increased in blood, urine & CSF C/F: Severe mental retardation & seizures No effective management

42. Glycinuria • Rare disorder • Serum glycine concentration normal/decreased, but very high amount (normal 0.5-1 g/day) excreted in urine • Due to defective renal reabsorption • characterized by increased tendency for formation of oxalate renal stones

43. Primary hyperoxaluria • Due to protein targetting defect (AR) • Normally, the enzyme alanine glyoxalate amino transferase is located in peroxisomes; but in these patients the enzyme is present in mitochondria • So, enzyme is inactive • Results in excess production of oxalates, comes in urine

45. Renal deposition of oxalates: nephrolithiasis,renal colic, hematuria • Extrarenal oxalosis: seen in heart, blood vessels & bone

46. Type 2 primary hyperoxaluria • Milder condition causing only urolithiasis • Results from deficient activity of cytoplasmic glyoxalate reductase/oxidase

47. Management : • To increase oxalate excretion by increased water intake • Minimise dietary intake of oxalates by restricting the intake of leafy vegetables, tea, beet-root etc.

49. Thank You