Glycine cleavage enzyme

These tetrahydrofolate derivatives serve as donors of one-carbon units in a variety of biosyntheses. Methionine is regenerated from homocysteine by transfer of the methyl group ofF -methyltetrahydrofolate, as will be discussed shortly. We shall see in Chapter 25 that some of the carhon atoms of purines are acquired from derivatives of N lO-formyltetrahydrofolate. The methyl group of thymine, a pyrimidine, comes from N, N lO-methylenetetrahydrofolate. This tetrahydrofolate derivative can also donate a one-carhon unit in an alternative synthesis of glycine that starts with CO2 and NH4 +, a reaction catalyzed by glycine synthase (called the glycine cleavage enzyme when it operates in the reverse direction). 

The one-carbon carrier N, N -methylenetetrahydrofolate is derived from reactions of the one-carbon pool (Chapter 27). [The term one-carbon pool refers to all single-carbon-containing metabolites (e.g., -CH3, -CHO, NH=C-, etc.) that can be utilized in biosynthetic reactions such as formation of purine and pyrimidine.] These reactions include oxidation of glycine by glycine cleavage enzyme complex (glycine synthase) ... 

Recent studies with bovine heart mitochondrial matrix preparations indicate that one of the major products of this pathway is octanoyl-ACP and these newly synthesized octanoyl moieties can be translocated directly to the lipoylation site of the glycine cleavage apo-H protein (S. Smith, 2007). Octanoylated mitochondrial proteins are the substrates for the enzyme lipoic acid synthase, which inserts two sulfur atoms at the C6 and C8 positions of the octanoyl moiety. These results are consistent with the hypothesis that one of the major roles of the mitochondrial FAS pathway in all eukaryotes is to ensure that an adequate supply of lipoyl moieties is always available to service the glycine cleavage enzyme and the alpha-ketoacid dehydrogenases that are essential to mitochondrial function. 

Mabrouk, G.M., Jois, M., and Brosnan, J.T., Cell signalling and the hormonal stimulation of the hepatic glycine cleavage enzyme system by glucagon, Biochem. J., 330, 759, 1998. 

Hyperammonemia may also result from congenital or acquired causes that are not related to inherited metabolic diseases. Examples of congenital causes include malformations such as portosystemic shunts, extrahepatic portal vein obstructions, and cirrhosis with portal hypertension. Transient hyperammonemia of the newborn (THAN) is typically identified in premature infants and does not appear to have a neurologic effect on those asymptomatic preterm infants [11]. Liver failure may also result in fulminant hyperammonemia. In severe liver failure, all of the enzymes expressed in the liver are deficient, resulting in complete impairment of the urea cycle as well as a deficiency of other important liver-specific enzymes snch as the glycine cleavage enzyme. 

FIGURE 40-3 Glycine cleavage system and some related reactions. Glycine and serine are readily interchangeable. Enzymes (1) Glycine cleavage system (2) and (4) Serine hydroxymethyltransferase (3) N5 10-methylenetetrahydrolate reductase. N5 I0-CH2-FH4, N5>10-methylenetetrahydrolate FH4, tetrahydrofolic acid. 

The glycine cleavage system is a group of four enzymes that together catalyze the following reaction ... 

Significant HMBPA accumulation indicates a metabolic bottleneck at the PanB-catalyzed hydroxymethylation step. Engineering the supply chain for methylene tetrahydrofolate, the cosubstrate of the PanB reaction, by overexpression of SerA and GlyA or of the enzymes of the glycine cleavage cycle drastically reduced HMBPA accumulation in favor of further increased (7 )-pantothenic acid production [177]. This result indicates that insufficient availability of the PanB cosubstrate is a major cause of unwanted side-product formation. 

Glycine cleavage system an enzyme system accounting for a major proportion of glycine metabolism in vertebrate liver. It is composed of 4 proteins 1. P-protein, which contains pyridoxal phosphate, 2. H-protein, which acts as a carrier and contains lipoic acid, 3. L-protein (lipoamide dehydrogenase) and 4. T-protein, a transferase dependent on tetrahydrofolate. The following reactions occur ... 

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