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 3rd aa 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 hydroxymethyl transferase 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. Serine hydroxy methyl transferase
From serine
Serine hydroxy methyl transferase
Serine
Glycine
THFA
N5,N10 methylene THFA

9. Glycine + acetaldehyde
From Threonine
Glycine can also be obtained from threonine, catalysed by threonine aldolase
Threonine aldolase
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. Glycine synthase complex, PLP
From CO2, NH3
N5,N10 Methylene THFA
Glycine synthase 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 Glyoxalate Glycine PLP
Glycine amino-transferase /
alanine glyoxalate amino transferase

16. Degradation of glycine
Glycine : oxidative deaminaion (by reversal of glycine synthase) : 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 glycine decarboxylase
Lipoamide containing amino methyltransferase
Methylene THFA synthesizing enzyme
NAD+ dependent lipoamide dehydrogenase
Major route for glycine breakdown in mammals

18. Glucogenic Pathway
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
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 : mg/dl
Serum creatine : mg/dl
Urine level:
Creatinine: gm/day
Creatine: 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 creatine in urine : in Muscular dystrophy

33. Glycine + Succinyl CoA Amino levulinate (ALA)
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
Chenodeoxy cholic acid + glycine Glycochenodeoxycholic acid

38. Benzoyl CoA + glycine Hippuric acid/benzoyl
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
Benzoyl CoA + 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 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