Propionyl-CoA-carboxylase

Propionic acidemia caused by propionyl CoA cetrboxylase deficiency causes severe ketosis amd acidosis, resulting in fedlure to thrive and menttd retardation, and is genei tdly fatal in infeuicy. Some reports of ketotic hyperglycinemia may cdso, with hindsight, be attributed to propionyl CoA carboxyltise deficiency. 

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Glncose-6-phosphatase Biotin (biocytin) CO, Propionyl-CoA carboxylase... 

Fatty acids with odd numbers of carbon atoms are rare in mammals, but fairly common in plants and marine organisms. Humans and animals whose diets include these food sources metabolize odd-carbon fatty acids via the /3-oxida-tion pathway. The final product of /3-oxidation in this case is the 3-carbon pro-pionyl-CoA instead of acetyl-CoA. Three specialized enzymes then carry out the reactions that convert propionyl-CoA to succinyl-CoA, a TCA cycle intermediate. (Because propionyl-CoA is a degradation product of methionine, valine, and isoleucine, this sequence of reactions is also important in amino acid catabolism, as we shall see in Chapter 26.) The pathway involves an initial carboxylation at the a-carbon of propionyl-CoA to produce D-methylmalonyl-CoA (Figure 24.19). The reaction is catalyzed by a biotin-dependent enzyme, propionyl-CoA carboxylase. The mechanism involves ATP-driven carboxylation of biotin at Nj, followed by nucleophilic attack by the a-carbanion of propi-onyl-CoA in a stereo-specific manner. 

Biotin is involved in carboxylation and decarboxylation reactions. It is covalently bound to its enzyme. In the carboxylase reaction, C02 is first attached to biotin at the ureido nitrogen, opposite the side chain in an ATP-dependent reaction. The activated C02 is then transferred from carboxybiotin to the substrate. The four enzymes of the intermediary metabolism requiring biotin as a prosthetic group are pyruvate carboxylase (pyruvate oxaloacetate), propionyl-CoA-carboxylase (propionyl-CoA methylmalonyl-CoA), 3-methylcroto-nyl-CoA-carboxylase (metabolism of leucine), and actyl-CoA-carboxylase (acetyl-CoA malonyl-CoA) [1]. 

Carboxylation of propionyl-CoA is accomplished by propionyl-CoA carboxylase (biotin, which is the carboxyl group carrier, serves as a coenzyme for this enzyme) the presence of ATP is also required. The methylmalonyl-CoA formed is converted by methylmalonyl-CoA mutase (whose coenzyme, deoxyadenosylcobalamin, is a derivative of vitamin B]2) to succinyl-CoA the latter enters the Krebs cycle. 

Makes propionyl-CoA, which is metabolized by propionyl-CoA carboxylase (biotin) and methylmalonyl-CoA mutase (B12) to give succinyl-CoA. 

Odd-chain fatty acids are an exception. While they are relatively rare in the diet, odd-chain-length fatty acids end up at propionyl-CoA (C3). Propionyl-CoA is carboxylated by propionyl-CoA carboxylase to give methylmalonyl-CoA. Methylmalonyl-CoA is rearranged to succinyl-CoA by the enzyme methylmalonyl-CoA mutase, a vitamin-B12-requiring enzyme. 

The way biotin participates in carbon dioxide fixation was established in the early 1960s. In 1961 Kaziro and Ochoa using propionyl CoA carboxylase provided evidence for 14C02 binding in an enzyme-biotin complex. With excess propionyl CoA the 14C label moved into a stable position in methyl malonyl CoA. In the same year Lynen found biotin itself could act as a C02 acceptor in a fixation reaction catalyzed by B-methylcrotonyl CoA carboxylase. The labile C02 adduct was stabilized by esterification with diazomethane and the dimethyl ester shown to be identical with the chemically synthesized molecule. X-ray analysis of the bis-p-bromanilide confirmed the carbon dioxide had been incorporated into the N opposite to the point of attachment of the side chain. Proteolytic digestion and the isolation of biocytin established the biotin was bound to the e-NH2 of lysine. 

Propionyl CoA carboxylase Odd-carbon fatty acids, Val, Alopecia (hair loss), bowel inflammation. 

Fatty acids with an odd number of C atoms are treated in the same way as normal fatty acids—i. e., they are taken up by the cell with ATP-dependent activation to acyl CoA and are transported into the mitochondria with the help of the carnitine shuttle and broken down there by p-oxidation (see p. 164). In the last step, propionyl CoA arises instead of acetyl CoA. This is first carboxylated by propionyl CoA carboxylase into fSj-methylmalonyl CoA [3], which—after isomerization into the (i ) enantiomer (not shown see p. 411)—is isomerized into succinyl CoA [4]. 

This enzyme [EC 6.3.4.10], also known as biotin— [propionyl-CoA-carboxylase] ligase and holocarboxylase synthetase, catalyzes the reaction of biotin with ATP and apo-[propanoyl-CoA carbon-dioxide ligase (ADP-forming)] to produce AMP, pyrophosphate, and propa-noyl-CoA carbon-dioxide ligase (ADP-forming). 

This enzyme [EC 4.1.1.41 ], also known as propionyl-CoA carboxylase, catalyzes the conversion of (5)-2-methyl-3-oxopropanoyl-CoA to propanoyl-CoA and carbon dioxide. The enzyme from Veillondla alcalescens is a biotinyl-protein, requires sodium ions, and acts as a sodium pump. 

POLYPHOSPHATE KINASE PROPIONYL-CoA CARBOXYLASE PROPIONYL-CoA SYNTHETASE... 

PROPIONYL-CoA CARBOXYLASE METHYLMALONYL-CoA DECARBOXYLASE METHYLMALONYL-CoA EPIMERASE d-METHYLMALONYL-CoA HYDROLASE... 

PROPIONYL-CoA SYNTHETASE PROPIONYL-CoA CARBOXYLASE PROPIONYL-CoA SYNTHETASE PRO-PROCHIRAL PROCHIRALITY CHIRALITY pro-R GROUP pro-S GROUP... 

Biotinidase (EC 3.5.1.12) is required for the recycling of biotin and for the utilization of protein bound biotin from the diet. Biotin (vitamin H) functions as a prosthetic group of four carboxylases in man the mitochondrial propionyl-CoA carboxylase,... 

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. 

Acetyl-CoA carboxylase Propionyl-CoA carboxylase Pyruvate carboxylase P-Methylcrotonyl-CoA carboxylase (8 carboxylation)... 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

Pyruvate carboxylase, which participates in gluconeogenesis and lipogenesis Acetyl-CoA carboxylase, which participates in fatty acid biosynthesis Propionyl-CoA carboxylase, which participates in isoleucine catabolism 3-Methylcrotonyl-CoA carboxylase, which participates in leucine catabolism... 

Hydroxypropionate / malyl-CoA cycle 10 7 NAD(P)H, but 1 FAD is reduced in the cycle Acetyl-CoA/propionyl-CoA carboxylase HCOJ Acetyl-CoA, pyruvate, succinyl-CoA Malonyl-CoA reductase, propionyl-CoA synthase, malyl-CoA lyase... 

H ydroxypropionate / 4- hydroxybutyrate cycle 9 6 NAD(P)H Acetyl-CoA/propionyl-CoA carboxylase HCOJ Acetyl-CoA, succinyl-CoA Acetyl-CoA/propionyl-CoA carboxylase", enzymes reducing malonyl-CoA to propionyl-CoA, methylmalonyl-CoA rnutase, 4-hydroxybutyryl-CoA dehydratase... 

This pathway results in the fixation of three molecules of bicarbonate, and forms pyruvate as the central carbon precursor molecule. The main C02-fixing enzyme is acetyl-CoA/propionyl-CoA carboxylase. 

The energy costs of the 3-hydroxypropionate/malyl-CoA cycle are high, with ten ATP required per triose phosphate (see Table 3.1). However, bicarbonate rather than C02 is the actual inorganic carbon species used by acetyl-CoA/propionyl-CoA carboxylase (this is discussed in Chapter 4). Moreover, as this enzyme is virtually irreversible and has a high affinity for bicarbonate, this cycle is expensive although kinetically effective. 

In this cycle, one molecule of acetyl-CoA is formed from two molecules of bicarbonate (Figure 3.5). The key carboxylating enzyme is the bifunctional biotin-dependent acetyl-CoA/propionyl-CoA carboxylase. In Bacteria and Eukarya, acetyl-CoA carboxylase catalyzes the first step of fatty acid biosynthesis. However, Archaea do not contain fatty acids in their lipids, and acetyl-CoA carboxylase cannot serve as the key enzyme of fatty acid synthesis rather, it is responsible for autotrophy. 

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