Regulation of the hepatic glycine-cleavage system.

The primary catabolic fate of glycine in mammals involves the hepatic glycine-cleavage system in which glycine is sequentially converted to CO,, NH,, NADH + H + , and NS, N"-methylenetetrahydrofolate (Fig. 1) (for review, see Kikuchi, 1973). This multi-enzyme reaction is located exclusively in the mitochondrial compartment (Motokawa 81 Kikuchi, 1971) and can be compared in several respects with the more common 2-0x0 acid dehydrogenase multienzyme complexes (i.e. the pyruvate, branched-chain 2-0x0 acid and 2-oxoglutarate dehydrogenases). While little is known about the regulation of hepatic glycine catabolism, the importance of understanding this process derives from observations that a variety of inherited genetic disorders are accompanied by pronounced hyperglycinaemia (e.g. concentrations of glycine 10-20 times normal in body fluids). Hyperglycinaemic states can be classified 'non-ketotic' (Nyhan, 1978) or 'ketotic' (Tanaka, 1975), and reflect primary defects in the glycine-cleavage system and secondary effects on glycine catabolism caused by disorders in other metabolic pathways (e.g. branched-chain amino, propionic or methylmalonic acid metabolism), respectively. Recent results from our laboratory have indicated that the metabolic flux through the hepatic glycine-cleavage reaction can be monitored effectively both in isolated mitochondrial systems (Hampson et al . , 1983, 1 9 8 4 ~ ) and in the isolated perfused rat liver (Hampson et al., 19846) by measuring the production of I4CO, from [ I-'4C]glycine. In isolated rat liver mitochondria metabolic conditions which result in the oxidation of the NAD(H) and NADP(H) oxidation-reduction couples caused rapid rates of [ 1 -''C]glycine decarboxylation (e.g. State 3 or uncouplers) while reducing conditions (e.g. respiratory chain inhibitors or strongly reducing substrates in State 4 ) led to inhibited rates of [ l-'4C]glycine decarboxylation. While manipulation of mitochondrial adenine nucleotide ratios per se did not correlate with the rate of glycine cleavage, changes in the aforementioned NAD(H) and NADP(H) oxidation-reduction couples exhibited very close correlations with the measured metabolic flux through the glycine-cleavage reaction. Short-chain-length fatty acids such as propionate caused a marked acceferation of glycine cleavage in rat liver