Glycine metabolism

Glycine
• Simplest
• No chiral carbon atoms
 Glycine
• Optically inactive
• Polar aminoacid
• Non-essential
• Glucogenic
• It is constituent of proteins
• Many special products are derived from glycine-
haem, creatine etc
• Glycine is also a neurotransmitter
• Contributes to 1 carbon pool
 Synthesis
• Non-essential amino acid
Synthesised from
• Serine
• Glyoxalate by transamination
• Choline
• Threonine
Glycine Synthesis
Serine hydroxyl methyl transferase
Transamination reaction

PLP
Synthesis from choline
 Choline

2H
Oxidation
[O]

Betaine

Demethylation CH3

CH3
O
Sarcosine
Demethylation
CH3

Glycine
Threonine aldolase
 Catabolic fate
Glucogenic amino acid
• Glycine cleavage complex
• Conversion to serine
• Deamination
Glycine cleavage complex/ glycine synthase

• Liver
 Glycine cleavage complex

• Multienzyme complex
• 4 proteins – 3 are enzymes
• P –protein- glycine decarboxylase PLP dependent
• T-protein- amino methyl transferase
• L-protein – Dihydrolipoamide dehydrogenase
• H-protein – carrier protein
Serine hydroxymethyl transferase

Pyruvate Glucogenic
 Deamination/Glycine oxidase
• Liver and kidney
 Special metabolic role of glycine
• Synthesis of haem
• Synthesis of purine nucleotide
• Synthesis of creatine
• Synthesis of glutathione
• Conjugating agent
• Neurotransmitter
Synthesis of haem

Glycine Succinyl CoA

ALA Synthase

Delta amino leuvulinic acid

(ALA)

Haem
Synthesis of purine nucleotide
Synthesis of Creatine
 Creatine
• Creatine phosphate is used as a storage form
of high energy phosphate in muscles.
 Phosphagens

• Storage form of high energy phosphates

• Creatine phosphate in vertebrates
• Arginine phosphate in invertebrates

-12.6 kJ/mol
 Creatinine
• Creatinine is formed in muscle from creatine
phosphate by a nonenzymatic dehydration and
loss of phosphate.
• The amount of creatinine produced is related to
muscle mass
• It remains remarkably constant from day to day.
• Creatinine is excreted by the kidneys
• Serum creatinine and creatinine clearance are
measure of renal function
Synthesis of glutathione

γ-Glutamylcysteinyl glycine
 Glutathione
• Tripeptide thiol
• Atypical peptide bond
Many important functions
• Reducing agent
• Used for conjugating drugs
• Used for transport of amino
acids across cell membrane
• Needed for leukotriene
synthesis
 Glutathione as reductant
• -SH group in glutathione is a hydrogen carrier
• Scavenges Hydrogen peroxide
• Important in protecting RBCs from the damage
caused by H2O2.
Glutathione
Glutathione
 Conjugation with glutathione
• A number of potentially toxic electrophilic drugs and
carcinogens thiopurine are conjugated to the
nucleophilic GSH
• The enzymes catalyzing these reactions are called
glutathione S-transferases
Meister’s cycle
 Glycine as conjugating agent

• Glycine also conjugates with metabolites and

pharmaceuticals
• Making them more water soluble and
excreted easily
• Eg bile acids glycocholic acid, hippuric acid
formed from the food additive benzoate
• Many drugs, drug metabolites, and other
compounds with carboxyl groups are excreted in
the urine as glycine conjugates.
Conjugating agent
 Glycine as Neurotransmitter
• Glycine is an inhibitory neurotransmitter in
brain stem and spinal cord
• Strychnine acts by blocking glycine receptors.
Inborn errors in the metabolism of glycine

Nonketotic hyperglycinemia/ Glycine encephalopathy

• A rare inborn error
• Known only in Finland
• Deficiency of glycine cleavage system
• Glycine accumulates in all body tissues including the
central nervous system
• Characterised by severe mental deficiency
• Patients do not survive infancy
 Primary hyperoxaluria Type I
• Autosomal recessive
• The deficiency of alanine-glyoxylate amino transaminase
• Failure to catabolize glyoxylate
• Oxidation of glyoxylate to oxalate and glycolate
• Results in urolithiasis, nephrocalcinosis

Glyoxylate reductase
 Primary hyperoxaluria Type II

• Autosomal recessive
• Deficiency of GR enzyme
• Milder form

Glyoxylate reductase
 Glycinuria
• Blood levels of glycine normal
• Urinary excretion of glycine high
• Defect in renal tubular reabsorption of glycine
• Autosomal dominant
• Oxalate excretion in urine normal
• Tendency to form urinary stones high
 Summary
• Synthesis – Serine, Threonine, Choline, Glyoxalate

• Catabolism – Glycine cleavage system, Serine, Deamination

Special metabolic role

• Haem

• Purine nucleotide

• Creatine

• Glutathione – RBC, drug detoxification, Meister cycle

• Conjugating agent

• Neurotransmitter

Inborn errors - Nonketotic hyperglycinemia, Primary hyperoxaluria