0-Acyl -malates

MALATE DEHYDROGENASE Malonyl-[acyl-carrier-protein],... 

Fatty acid synthesis and degradation. Fatty acids are synthesized in the cytosol by the addition of two-carbon units to a growing chain on an acyl carrier protein. Malonyl CoA, the activated intermediate, is formed by the carboxylation of acetyl CoA. Acetyl groups are carried from mitochondria to the cytosol as citrate by the citrate-malate shuttle. In the cytosol, citrate is cleaved to yield acetyl CoA. In addition to transporting acetyl CoA, citrate in the cytosol stimulates acetyl CoA carboxylase, the enzyme catalyzing the committed step. When ATP and acetyl CoA are abundant, the level of citrate increases, which accelerates the rate of fatty acid synthesis (Figure 30.8). 

Apart from the true Claisen condensations discussed in the previous section in which the electrophilic reaction partner is another thioester, a number of enzymes also catalyze related Claisen-like condensations in which an acyl-CoA-based nucleophile reacts with other electrophilic carbonyl groups such as ketones, aldehydes, and the carboxylate group of carboxy-biotin. The most important examples of such enzymes are hydroxymethylglutaryl-CoA (HMG-CoA) synthase, citrate and homocitrate synthase (HCS), malate and ct-isopropylmalate synthase (ct-IPMS), and the biotin-dependent acetyl- and propionyl-CoA carboxylases. 

FIG. 4.2 Malate metabolism in mitochondria from body wall muscle of adult Ascaris smm. (1) Fumarase (2) malic enzyme (3) pyruvate dehydrogenase complex (4) complex I (5) succinate-coenzyme Q reductase (complex II, fumarate reductase) (6) acyl CoA transferase (7) methylmalonyl CoA mutase (8) methyl-malonyl CoA decarboxylase (9) propionyl CoA condensing enzyme (10) 2-methyl acetoacetyl CoA reductase (11) 2-methyl-3-oxo-acyl CoA hydratase (12) electron-transfer flavoprotein (13) 2-methyl branched-chain enoyl CoA reductase (14) acyl CoA transferase. 

Displacement on the triflate 197 with oxygen nucleophiles allows immediate access to (7 )-malic acid derivatives. Potassium propionate or potassium benzoate cleanly inverts the stereocenter of 197b to give 0-acyl (i )-malates 200 in moderate yield [74]. 

Several syntheses have been reported implementing this strategy for preparing useful quantities of (i )-malic acid derivatives. Acylation of dimethyl (i )-tartrate (889) affords 890. Conversion of the 3-hydroxyl to chloride followed by dehalogenation with tri- -butyltin hydride furnishes the 0-acetyl (i )-malate (892). Acidic hydrolysis of the acetyl group gives dimethyl (i )-malate itself (203) (Scheme 130) [197]. 

KeUy,D.P.,Goidon,J.I.,Alpeis,R. Strauss,A.W.(1989)y. BiW. Chem. 264, 18921 18925, The tissue-specific expression and developmental regulation of two nuclear genes encoding rat mitochondrial proteins. Medium chain acyl-CoA dehydrogenase and mitochondrial malate dehydrogenase. 

The peroxisomal membrane forms a permeability barrier for a wide variety of metabolites required for and formed during fatty add P-oxidation (succinate, malate, acetylcarnitine, carnitine, 2-oxoglutarate, isocitrate and oxaloacetate). Continuous P-oxidation depends on the availability of acyl-CoA, NAD% NADPH, free coenzyme A and on export of acetyl groups. During P-oxidation of fatty acids, NAD is reduced to NADH. For continuation of P-oxidation, NADH must be re-oxidised to NAD. Evidence for a crucial role of intraperoxiso-mal NAD came from van Roermund et al. (1995). 

Enzymes (1) Lipases (2) Fatty acid thiokinase (3) Acyl CoA dehydrogenase (4) Crotonase (5) jS-Hydroxyacyl CoA (6) )5-Ketoacyl thiolase (7) Citrate synthetase (8) Aconitase (9) Isocitrate lyase (10) Malate synthetase (11) Malate dehydrogenase (12) Catalase (13) Succinate dehydrogenase (14) Fumarase (15) Malate... 

---