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

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

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.

Glycine metabolism

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

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

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

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

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

Glycine synthase complex, PLP From CO2, NH3 N5,N10 Methylene THFA Glycine synthase complex, PLP THFA CO2 + NH3 Glycine NADH + H+ NAD+

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

From Glyoxalate pyruvate alanine Glyoxalate Glycine PLP Glycine amino-transferase / alanine glyoxalate amino transferase

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

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

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

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

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

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

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

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

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

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

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

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

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)

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)

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

Glutathione

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

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

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

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

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

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

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

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

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

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.

Thank You