Malonyl co-enzyme

Haan EA, Scholem RD, Croll HB, Brown GK Malonyl co-enzyme A decarboxylase deficiency. Clinical and biochemical findings in a second child with a more severe defect. Eur J Pediatr 1986 144 567-570... 

MacPhee GB, Logan RW, Mitchell JS, Howells DW, Tsotsis E, Thorburn DR. Malonyl co-enzyme A decarboxylase deficiency. Arch Dis Child 1993 69 433-436... 

By 1960 it was clear that acetyl CoA provided its two carbon atoms to the to and co—1 positions of palmitate. All the other carbon atoms entered via malonyl CoA (Wakil and Ganguly, 1959 Brady et al. 1960). It was also known that 3H-NADPH donated tritium to palmitate. It had been shown too that fatty acid synthesis was very susceptible to inhibition by p-hydroxy mercuribenzoate, TV-ethyl maleimide, and other thiol reagents. If the system was pre-incubated with acetyl CoA, considerable protection was afforded against the mercuribenzoate. In 1961 Lynen and Tada suggested tightly bound acyl-S-enzyme complexes were intermediates in fatty acid synthesis in the yeast system. The malonyl-S-enzyme complex condensed with acyl CoA and the B-keto-product reduced by NADPH, dehydrated, and reduced again to yield the (acyl+2C)-S-enzyme complex. Lynen and Tada thought the reactions were catalyzed by a multifunctional enzyme system. 

For this group of aminomutases PLP is required as a second coenzyme. Third, X is attached via a carbon atom the enzymes are called mutases. Methyl-malonyl-Co mutase is required for catabolism of propionate in the human body, and is one of only two known vitamin B12-... 

I ollowing the formation of malonyl Co.A, another nucleophilic acy) substitution reaction occurs in step 4 to form the more reactive malonyl ACP, thereby binding the malonyl group to an ACP arm of the multicnzyme synthase. At this point, both acetyl and malonyl groups are bound to the enzyme, and the stage is set for their condensation. 

Acyl carrier protein Acyl transferase Malonyl transferase Co-enzyme A... 

The polyketide synthases and peptide synthetases catalyze an unusually large number of reactions. 6-Methylsalicylic acid synthase, which produces 6-methylsalicylic acid from acetyl Co A, malonyl Co A and NADPH, for instance, carries out a total of thirteen reactions. The peptide antibiotic synthetases activate each of the amino acids involved in the formation of the peptides by a two step mechanism at a specific peripheral domain of the enzyme protein and catalyze also linkage of the activated amino acids by sequential transpeptidation. In the case of gramicidin S synthetase for example, there are twenty-one different reactions carried out by two multifunctional enzyme proteins. 

The conversion of long-chain fatty acids into ketone bodies is schematically drawn in Fig. 14.1. The whole process takes place in the liver cell. Long-chain fatty acids are taken up by the cell and are converted into co enzyme A esters (AS). Carnitine has to be brought into the cell by its plasma membrane transporter. Once inside the intermembrane space, acyl-CoA and carnitine react under the influence of CPTl, a membrane-bound enzyme, the activity of which is regulated by the levels of malonyl-CoA and glucagon. This is the key regulating step of the fatty acid yff-oxidation. 

The elaborate cobaloxime system (1) has been synthesized (in 7% yield) with a view to modelling the active site of the vitamin Big dependent enzyme methyl-malonyl Co-A mutase. Irradiation of (1) for short periods in methanol causes... 

In type II FAS, each reaction has to be catalyzed by a monofiinctional polypeptide. In type II enzyme systems, 4 -phosphopantheine, which is involved in binding malonyl from malonyl-Co A, is attached to a 10,000 dalton apoprotein. In type I FAS, this cofactor is an integral part of a >180,000 dalton subunit. Another difference is that type II systems have a holoprotein known as acyl carrier protein (ACP) which functions like CoA in animals and fungi, and all FAS reactions are carried out on ACP-bound substrates. 

Coumaroyl-CoA is produced from the amino acid phenylalanine by what has been termed the general phenylpropanoid pathway, through three enzymatic conversions catalyzed by phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), and 4-coumarate CoA ligase (4CL). Malonyl-CoA is formed from acetyl-CoA by acetyl-CoA carboxylase (ACC) (Figure 3.2). Acetyl-CoA may be produced in mitochondria, plastids, peroxisomes, and the cytosol by a variety of routes. It is the cytosolic acetyl-CoA that is used for flavonoid biosynthesis, and it is produced by the multiple subunit enzyme ATP-citrate lyase that converts citrate, ATP, and Co-A to acetyl-CoA, oxaloacetate, ADP, and inorganic phosphate. ... 

Correct answer = D. Malonyl CoA (three carbons) is synthesized from acetyl CoA (two carbons) by the addition of CO2, using the enzyme acetyl CoA carboxylase. Because CO. is subsequently removed during fatty acid synthesis, the radioactive label will not appear at any position in newly synthesized fatty acids. 

Step 1 of Figure 29.13 Carboxylation GTuconeogcnesis begins with the carboxyl-ation of pyruvate to yield oxaloacetate. TTie reaction is catalyzed by pyruvate carboxylase and requires ATP, bicarbonate ion, arid the coenzymc biotin, which acts as cj j ciiiiei to transport CO2 to tlie enzyme active site. The mechanism is analogous to that of step 3 in fatty-acid biosynthesis fFigine 29.6), in which acetyl Co.A is caiboxylated to yheld malonyl CoA. 

STEPS 3-4 Carboxylation and acyl transfer. The third priming reaction again starts with acetyl CoA, which is carboxylated by reaction with HCOa and ATP to yield malonyl CoA plus ADR This step involves the coenzyme biotin, which is bonded to the lysine residue of acetyl CoA carboxylase enzyme and acts as a carrier of CO. The enolate ion of acetyl CoA reacts with carboxylated biotin and transfers the CO2 group in a nucleophilic acyl substitution reaction. 

The synthesis of malonyl CoA is catalyzed by acetyl CoA carboxylase, which contains a biotin prosthetic group. The carboxyl group of biotin is covalently attached to the t amino group of a lysine residue, as in pyruvate carboxylase (p. 462) and propionyl CoA carboxylase (p. 627).. As with these other enzymes, a carboxybiotin intermediate is formed at the expense of the hydrolysis of a molecule of ATP. The activated CO group in this intermediate is then transferred to acetyl CoA to form mal-onvl CoA. 

C02-biotin-enzyme 4- ADP + P CO -biotin-enzyme + acetyl CoA -----> malonyl CoA + biotin-enzyme... 

The major product of the fatty acid synthase is palmitate. In eukaryotes, longer fatty acids are formed by elongation reactions catalyzed by enzymes on the cytoplasmic face of the endoplasmic reticulum membrane. These reactions add two-carbon units sequentially to the carboxyl ends of both saturated and unsaturated fatty acyl CoA substrates. Malonyl CoA is the tuu-carbon donor in the elongation of fatty acyl Co As. Again, condensation is driven by the decarboxylation of malonyl CoA. 

Fatty acids have predominantly even numbers of carbon atoms because they are effectively formed from acetyl (C2) units, which are derived from glucose in the presence of various enzymes, coenzymes and carrier proteins. An overall scheme for saturated fatty acid biosynthesis is presented in Fig. 2.13, in which it can be seen that the first step is the formation of acetyl coenzyme A (often abbreviated to acetyl-CoA). One molecule ofacetyl-CoA undergoes addition of CO, to form malonyl-CoA, while the acetyl group on another molecule is transferred to an enzyme (fatty acid synthase). The malonyl unit (C3) is added to the enzyme-bound acetyl unit, which produces a butyryl group following loss of C02, dehydration and reduction. Six further steps of combined malonyl addition, decarboxylation, dehydration and reduction occur to yield palmitate (C16). Higher acids are built from palmitate in a similar... 

The FA elongation stage is catalyzed by P-ketoacyl synthase III (KAS III), a single polypeptide enzyme with several catalytic sites, which allows the enzyme to promote different reactions during this stage (Voelker Kinney, 2001). The condensation of malonyl-ACP and acetyl-CoA to yield 3-ketobutyryl-ACP and CO is the first reaction. The second reaction is the reduction of 3-ketobutyl-ACP to 3-hydroxylacyl-... 

The homolytic cleavage of the Co - C bond of the protein-boimd organo-metallic cofactor AdoCbl (2) is the initial step of the coenzyme Bi2-catalyzed enzymatic reactions. Halpern quoted that adenosyl cobamides can be considered as reversibly functioning sources for organic radicals [119]. A neutral aqueous solution of 2 is remarkably stable with a half-Ufe of 10 s (in the dark at room temperature), but decomposes, mainly with the homolysis of the Co-C bond, at higher temperatures [119,123]. The coenzyme B12-catalyzed enzyme reactions occur with maximal rates of approximately 100 s [173,239]. Rapid formation of Co(ll)corrins occurs only with addition of substrate to a solution of holoenzyme (or of apoenzymes and 2), as demonstrated in most of the known coenzyme Bi2-dependent enzymes, e.g., in methyl-malonyl-CoA mutase [121], glutamate mutase [202] and ribonucleotide reductase [239]. 

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