GLYCINE METABOLISM

GLYCINE METABOLISM

1. Gandham.Rajeev Email:[email protected] Metabolism of Glycine

2. Simple amino acid. Non essential amino acid. Optically inactive due to absence of asymetric carbon atom. Chemistry

3. Glycine is actively involved in the synthesis of many specialized products ( heme , purines , creatine etc. Required for synthesis of serine & glucose. Involved in one-carbon metabolism . Glycine is the most abundant amino acid normally excreted into urine ( 0.5-1.0 g/g creatinine).

4. Nutritional - non-essential amino acid. Metabolically - glucogenic amino acid. Glycine is one among the commonest amino acids found in protein structure. Glycine is mostly present in the interior structure of protein. Collagen contains very high (about 30%) content of glycine.

5. Glycine metabolism

6. Synthesis of Glycine Glycine is synthesized from: From Serine From Threonine From CO 2 , NH 3. From Glyoxalate .

7. From serine Glycine is synthesized from serine by the enzyme serine hydroxymethyl transferase which is dependent on tetrahydrofolate ( THF).

8. From serine Serine Glycine Serine hydroxy methyl transferase , PLP THFA N5,N10 methylene THF NAD + NADH + H +

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

10. Glycine can be synthesized by the glycine synthase reaction from CO2 , NH3 & one carbon unit. This is the reversal of the glycine cleavage system. It is a multienzyme complex . It needs the co-enzymes, NAD , lipoamide , tetrahydrofolic acid & PLP. From CO2, NH3

11. From CO2, NH3 CO2 + NH3 Glycine Glycine synthase complex, PLP N 5 ,N 10 Methylene FH 4 FH 4 NAD + NADH + H +

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

13. From Glyoxalate Glyoxalate Glycine Glutamic acid α - Ketoglutarate Glycine amino- transferase PLP

14. D egradation of glycine Glycine undergoes oxidative deaminaion by glycine synthase to liberate NH4 + , CO 2 & one carbon fragment as N 5 , N 10 methylene THF. This provides a major route for glycine breakdown in mammals.

15. Glycine Glycine synthase , PLP N 5 ,N 10 Methylene FH 4 FH 4 NAD + NADH + H + CO 2 + NH 3 D egradation of glycine

16. It is a multienzyme complex. It requires co-enzymes - PLP , NAD, THFA. PLP-dependent glycine decarboxylase. Lipoamide containing amino methyltransferase Methylene THFA synthesizing enzyme. NAD + dependent lipoamide dehydrogenase . Glycine Synthase complex

17. Glucogenic Pathway Glycine is mainly channelled into the glucogenic pathway by getting first converted to serine. This is the reversal of serine hydroxy methyltransferase reaction. The serine is then converted to pyruvate by serine dehydratase

18. Glycine is reversibly converted to serine by THF dependent serine hydroxymethyl transferase . Pyruvate produced from serine by serine dehydratase , serves as a precursor for glucose. Glycine Serine Serine hydroxy methyl transferase , PLP THFA N5,N10 methylene THF NAD + NADH + H +

19. Serine is degraded to glyoxylate which undergoes transamination to give back to glycine. Glyoxylate is also converted to oxalate , an excretory product & formate enter one carbon pool.

20. Synthesis of specilized products Formation 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.

21. It is a tri-peptide , containing glutamic acid, cysteine , glycine . Present as reduced form (GSH) & oxidized form (GSSG). Synthesis of glutathione

22. Glutathione

23. 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 Chenodeoxy cholic acid + glycine Glycochenodeoxycholic acid

24. Benzoic acid is used in small amounts as preservative in foods. Glycine is used for detoxification of benzoic acid to form hippuric acid. Benzoic acid + glycine Hippuric acid

25. Synthesis of heme Glycine condenses with succinyl CoA to δ -amino levulinate which serves as a precursor for heme synthesis. Glycine + Succinyl CoA Amino levulinate (ALA) ALA S ynthase

26. Biosynthesis of creatine Creatine is present in the tissues as a high energy compound, phosphocreatine & as free creatine . Three amino acids glycine, arginine & methionine are required for creatine formation.

27. 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 arginine-glycine transamidinase to produce guanidoacetate ( glycocyamine ). Steps in biosynthesis of creatine

28. Step-2: S- Adenosylmethionine ( active methionine ) donates methyl group to guanidoacetate ( glycocyamine ) to produce creatine . This reaction occurs in liver. Step-3: Creatine is reversibly phosphorylated to phosphocreatine ( creatine phosphate ) by creatine kinase.

29. It is stored in muscle as high energy phosphate. Serves as an immediate store of energy in the muscle Step-4: The creatine phosphate may be converted to its anhydride, creatinine . It is a non-enzymatic spontaneous reaction. Creatinine is excreted in urine.

30. Clinical Applications Normal serum creatinine level: 0.7 - 1.4 mg/dl. Serum creatine level: 0.2 - 0.4 mg/dl. Creatinine level in blood is a sensitive indicator of renal function. In muscular dystrophies , blood creatine & urinary creatinine are increased. The enzyme CK is elevated in MI.

31. Urine level: Creatinine: 1 - 2 gm/day. Creatine : 0 - 50 mg/day. Creatinine coefficient: Males: 20 - 30 mg/kg/24hrs. Females: 10 - 20 mg/kg/24hrs. Creatinine Clearance: Males: 90 - 130 ml/min. Females: 80 - 120 ml/min .

32. Excretion of creatinine is constant for an individual depends on muscle mass. Creatinine Clearance – measure of GFR. Normally , urine contains – creatine (less). Creatinuria – increased excretion of creatine in urine. Muscular dystrophy, Hypogonadism , Hyperthyroidism, DM & Stravation .

33. Glycine as a Neurotransmitter Glycine is seen 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.

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

35. Metabolic disorders of glycine It is due to defect in glycine cleavage system. Glycine level is increased in blood, urine & CSF . Severe mental retardation & seizures are seen. There is no effective management.

36. Glycinuria This is a rare disorder. Serum glycine concentration is normal , but very high amount ( normal 0.5-1 g/day ) is excreted in urine. It is due to defective renal reabsorption. It is characterized by increased tendency for formation of oxalate renal stones. U rinary oxalate level is normal in these patients

37. Primary hyperoxaluria It is due to protein targetting defect. 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. It characterized by increased urinary oxalate resulting in oxalate stones.

38. Deposition of oxalate ( oxalosis ) in various tissues is observed. The urinary oxalate is of endogenous origin & not due to dietary consumption of oxalate. Primary hyperoxaluria is due to a defect in glycine transaminase coupled with impairment in glyoxalate oxidation to formate .

39. Type 2 primary hyperoxaluria It is a milder condition causing only urolithiasis & results from deficient activity of cytoplasmic glyoxalate reductase . The management is to increase oxalate excretion by increased water intake. Minimise dietary intake of oxalates by restricting the intake of leafy vegetables, tea , beet-root etc.

40. References Textbook of Biochemistry-u Satyanarayana Textbook of Biochemistry-DM Vasudevan

41. Thank You