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Metabolism of Glycine (Part-2)- Metabolic role and clinical significance
Although nutritionally glycine is a non-essential amino acid but functionally it is very essential. The important functions of Glycine can be summarized as follows
i) As a constituent of protein
Glycine being a simple amino acid is found where the polypeptide bends as in beta bends or loops.
A striking characteristic of collagen is the occurrence of glycine residues at every third position of the triple helical portion of the alpha chain. This is necessary because glycine is the only amino acid small enough to be accommodated in the limited space available down the central core of the triple helix. This repeating structure, represented as (Gly-X-Y)n (figure-1), is an absolute requirement for the formation of the triple helix. While X and Y can be any other amino acids, about 100 of the X positions are proline and about 100 of the Y positions are hydroxy proline. Proline and hydroxy proline confer rigidity on the collagen molecule.
Figure-1- Glycine is the most abundantly found amino acid in the structure of collagen. Every third amino acid in the structure of alpha helix is glycine.
ii) One carbon donor
The major pathway of glycine catabolism involves the cleavage of glycine to form CO2, NH4+ and N5N10 Methylene tetra hydro folate (Figure-2). Hence it acts as a donor of one carbon fragment.
Figure-2- The reaction is catalyzed by glycine cleavage system, N5,N10 Methylene tetra hydro folate acts as a carrier of one carbon fragment
iii) Synthesis of Glutathione
Glutathione is a tripeptide containing three amino acids- Glutamic acid, cysteine and glycine (gamma glutamyl cysteinyl glycine) – Figure-3. It is an important reducing agent, helps in maintaining the integrity of the red blood cells; also acts as a coenzyme in many reduction reactions.
Figure-3- Structure of glutathione, GSH represents the reduced form of glutathione, the –SH group is contributed by cysteine
iv) Synthesis of creatine
Creatine (methyl guanido acetic acid ) is synthesized from three amino acids-Methionine, arginine and glycine. Methyl group is donated by Methionine; guanido group is contributed by Arginine and Acetic acid group comes from glycine. Creatine is stored in the muscle in the phosphorylated from- Creatine-P, a high energy compound. Creatinine is the anhydrous form of creatine (figure-4)
Figure-4- Role of glycine in the synthesis of creatine. Creatine –P also called phosphocreatine, is a high energy compound that can be non enzymatically converted to creatinine, the excretable form of creatine.
v) Synthesis of purine nucleotide
Glycine contributes its entire structure for the formation of C4, C5 and N7 of purine nucleus (figure-5)
Figure-5- C4,C5 and N7 are derived form Glycine. Three amino acids – Glycine, aspartic acid and glutamine, contribute towards formation of purine ring.
vi) Synthesis of bile salts
Cholyl co A derived from cholesterol conjugates with glycine to form Glycocholic acid, a bile acid which is secreted in the bile in the form of sodium salt- Sodium glycocholate(figure-6).
Figure- 6-Taurene is derived from cystiene. Glycocholic acid, tauro and glycochenodeoxy cholic acid are primary bile acids. The primary bile acids are converted to secondary bile acids by 7-Alpha dehydroxylation and deconjugation. Deoxy cholic acid and lithocholic acid are secondary bile acids.
Aromatic compounds like benzoic acid obtained from diet are detoxified by conjugation with glycine to form hippuric acid (figure-7) which is excreted in urine. This reaction takes place exclusively in liver. Hippuric acid excretion test is carried out to determine the functional status of liver.
Many drugs, drug metabolites, and other compounds with carboxyl groups are excreted in the urine as glycine conjugates.
Figure-7- Sodium benzoate is given as a loading dose and the amount of hippuric acid excreted in urine is estimated to determine the functional status of liver.
viii) Synthesis of heme
The two starting materials for heme synthesis are succinyl-CoA, derived from the citric acid cycle in mitochondria, and the amino acid glycine. By a series of reactions heme is synthesized (figure-8) that can be used for the synthesis of hemoglobin and other hemo proteins.
Figure-8- By a series of steps porphoblinogen is converted to heme.
ix) Synthesis of Glucose
Glycine is glucogenic in nature. During the course of its metabolism it is converted to serine (figure-9) which is non oxidatively deaminated to from pyruvate. Pyruvate is further channeled towards pathway of gluconeogenesis.
Figure-9- Glycine and serine are inter convertible. Serine forms pyruvate upon non oxidative deamination which is a substrate for gluconeogenesis.
x) Glycine as a neurotransmitter
Glycine itself acts as neurotransmitter to regulate brain activities.
Non ketotic hyperglycinemia- It is due to defect in the glycine cleavage system. Glycine level is found to be higher in blood, C.S.F and urine. Severe mental retardation and convulsions are observed. There is no permanent cure for this disorder only symptomatic treatment can be given.
The disease is characterized by excessive excretion of glycine in urine. Urinary excretion of glycine ranges from 600-1000 mg/dl. Plasma level of glycine remains normal.
Biochemically there is no enzyme deficiency. The defect is attributed to renal tubular reabsorption of glycine. The tendency to oxalate stone formation is increased.
The disorder is characterized by continuous high excretion of oxalates. Biochemically it is a protein targeting effect. There is excessive oxalate formation from Glycine. The patients present with progressive bilateral calcium oxalate urolithiasis, recurrent urinary infections and renal damage.
Death occurs in childhood or early adult life from renal failure or hypertension.
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