Propionic acid propionyl coenzyme

The oxidation of the side chain of 5j -cholestane-3a,7a,12a-triol to yield cholic acid or rather cholyl coenzyme A entails an co-oxidation followed by a jS-oxidation (Fig. 2). Early investigations (71,72) showed that the mitochondrial fraction of rat and mouse liver homogenate catalyzed the conversion of 5jS-cholestane-3a,7a, 12a-triol into 5/5-cholestane-3a,7a, 12a,26-tetrol and, when supplemented with the 100,000g supernatant fluid, the further transformation of 5j -cholestane-3a,7a,12a,26-tetrol into 3a,7a,12a-trihydroxy-5/9-cholestanoic acid (Fig. 2). Suld et al. (72) showed that the conversion of 3a,7a,12a-trihydroxy-5/5-cholestanoic acid into cholic acid (cholyl coenzyme A), catalyzed by the mitochondrial fraction fortified with the 100,000g supernatant fluid, occurs with the release of propionic acid (propionyl coenzyme A). 

In addition to phenylacetonitrile and fluorene, various active methylene compounds such as indene, propiophenone, phenyl propionate, benzyl phenylacetate afforded the corresponding carboxylated products by the carboxylation reaction with La(0 Pr)3-Ph-N=C=0-C02 system. Of fundamental and practical importance is that S-benzyl thiopropionate was effectively carboxylated into a thioester of 2-methylmalonate in a good yield, since this reaction is related to the biological carboxylation of propionyl coenzyme A with a biotin enzyme. Other thioesters were also carboxylated similarly, where successful examples were thioesters of phenylacetic, acetic, and isovaleric acids carrying active methylene and methyne groups, respectively. 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Propionyl-coenzyme A, propionyl-CoA activated propionic acid, formed by attachment of coenzyme A to propionic acid by a thioester linkage. Pro-... 

Biotin serves as the prosthetic group of several enzymes that catalyse the transfer of carbon dioxide from one substrate to another. In animals there are three biotin-dependent enzymes of particular importance pyruvate carboxylase (carbohydrate synthesis from lactate), acetyl coenzyme A carboxylase (fatty acid synthesis) and propionyl coenzyme A carboxylase (the pathway of conversion of propionate to succinyl-CoA). The specific role of these enzymes in metabolism is discussed in Chapter 9. 

CoA transferase. CoA transferase catalyzes a reversible transfer of coenzyme A from propionyl-CoA or acetyl-CoA to succinate, resulting in the formation of propionic acid. The reaction can be described as follows ... 

Propionyl-CoA is first carboxylated to form the d stereoisomer of methylmalonyl-CoA (Pig. 17—11) by propionyl-CoA carboxylase, which contains the cofactor biotin. In this enzymatic reaction, as in the pyruvate carboxylase reaction (see Pig. 16-16), C02 (or its hydrated ion, HCO ) is activated by attachment to biotin before its transfer to the substrate, in this case the propionate moiety. Formation of the carboxybiotin intermediate requires energy, which is provided by the cleavage of ATP to ADP and Pi- The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its l stereoisomer by methylmalonyl-CoA epimerase (Pig. 17-11). The L-methylmal onyl -CoA then undergoes an intramolecular rearrangement to form succinyl-CoA, which can enter the citric acid cycle. This rearrangement is catalyzed by methylmalonyl-CoA mutase, which requires as its coenzyme 5 -deoxyadenosyl-cobalamin, or coenzyme Bi2, which is derived from vitamin B12 (cobalamin). Box 17—2 describes the role of coenzyme B12 in this remarkable exchange reaction. 

This enzyme s role in humans is to assist the detoxification of propionate derived from the degradation of the amino acids methionine, threonine, valine, and isoleucine. Propionyl-CoA is carboxylated to (5 )-methylmalonyl-CoA, which is epimerized to the (i )-isomer. Coenzyme Bi2-dependent methylmalonyl-CoA mutase isomerizes the latter to succinyl-CoA (Fig. 2), which enters the Krebs cycle. Methylmalonyl-CoA mutase was the first coenzyme B -dependent enzyme to be characterized crystallographically (by Philip Evans and Peter Leadlay). A mechanism for the catalytic reaction based on ab initio molecular orbital calculations invoked a partial protonation of the oxygen atom of the substrate thioester carbonyl group that facilitated formation of an oxycyclopropyl intermediate, which connects the substrate-derived and product-related radicals (14). The partial protonation was supposed to be provided by the hydrogen bonding of this carbonyl to His 244, which was inferred from the crystal structure of the protein. The ability of the substrate and product radicals to interconvert even in the absence of the enzyme was demonstrated by model studies (15). 

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