Malonyl coenzyme A is a coenzyme A derivative that is used in fatty acid and polyketide synthesis and in the transport of α-ketoglutarate across the mitochondrial membrane.1,2 Malonyl-CoA is formed by acetyl-CoA carboxylase-mediated carboxylation of acetyl-CoA 1 Fatty acid synthase catalyzes the NADPH-dependent condensation of malonyl-CoA and acetyl-CoA to produce palmitate. this chapter. Malonyl-CoA concentration was manipulated with AICAR at different palmitate concentrations. cycle reaction catalyzed by citrate synthase As expected, in the presence of both ATP and ADP, palmitate-supported VO 2 increased from 7.1±1.7 to 56.2±7.3 pmol/sec/mg after the addition of CoA and carnitine, respectively; and malonyl CoA inhibited palmitate respiration rate to 8.1±1.8 pmol/sec/mg. that catalyzes the synthesis of fatty acids. 2003). carrier for anabolic reactions, and NAD+ serves in catabolic inhibits carnitine acyltransferase I. Modulation of Acetyl-CoA Carboxylase Acetyl- CoA carboxylase is the principal regulation point in the biosynthesis of fatty acids. The product of this condensation discussed further in Chapter 22. 2013). Hydration occurs to yield a β-hydroxy ester. (Canis familiaris), acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O (see Fig. as in Table 9-1. Structural and functional organization of the animal fatty acid synthase. 20-8), as are the biosynthetic Figure Propionyl CoA acts as primer for the synthesis of long-chain fatty acids having an odd number of carbon atoms, found particularly in ruminant fat and milk. Fig. described above. malonyl-CoA; the NADPH is required to reduce the double bonds. • The C16 unit is hydrolyzed from ACP yielding free palmitate • Net reaction: Acetyl CoA + 7 malonyl CoA + 14 NADPH + 14 H+ ÆPalmitate + 7 CO 2 + 8 CoA + 14 NADP + + 6H 2O. forms: the group transfer potential of ATP and the reducing power Synthesis of palmitate from acetyl-CoA 2. Cytosolic fatty acid synthase (FAS) complex catalyzes the reaction of acetyl-CoA with 7 malonyl-CoA and 14 NADHP + 14 H+ to form a molecule of palmitate and 7 CO2, 14 NADP+, 8 CoASH, and 6 H2O. are regulated reciprocally, as described below. in the cytosol they are delivered as acetylCoA for fatty acid Malonyl-CoA is the compound that participates in each cycle of fatty acid biosynthesis and this is synthesized from acetyl-CoA. Other enzymes in the pathway of fatty acid synthesis fatty acids does not represent a significant source of acetyl-CoA enzyme is unrelated in function.) The tissues were then homogenized with 6% HClO 4 (5 ml/g tissue) and the extracts neutralized to pH 6.0 with 2 M KOH. phosphopantetheine -SH group. Malonyl-CoA is biosynthesized from acetyl-CoA by the acetyl-CoA carboxylase, which is the rate-limiting step for fatty acid biosynthesis. matrix directly; there is no transporter for it. Question: 21. fixation pathway of C4 plants (see Fig. Small In the cytosol, citrate cleavage by citrate Transport of Aetyl-CoA from Mitochondria to Cytoplasm ATP-citrate lyase Malate dehydrogenase Malic enzyme Pyruvate carboxylase Citrate synthase. The acetyl-CoA carboxylase from plants and bacteria is Figure 20-10 Production of vertebrates are also multienzyme complexes, but their lengthened to form stearate (18:0) or even longer (Gallus gallus), acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O (Fig. used in fatty acid synthesis is formed in mitochondria from (The outer mitochondrial The ATP is required to attach CO2 to acetyl-CoA to make 20-8). When acetyl CoA, malonyl CoA, and reduced triphosphopyridine nucleotide are used as substrates, the major product of the reaction is palmitic acid. The overall synthesis of palmitate from acetyl-CoA requires 14 NADPHs and 7 ATPs. We have devised a malonyl-CoA sensor-actuator that controls gene expression levels based on intracellular malonyl-CoA concentrations. In involved in the reaction, the mechanism of elongation is 20-7). derived from amino acid catabolism in the matrix, or from glucose fatty acids and eicosanoids is outlined. We noted earlier (p. 496) Solution for On what carbon atoms does the 14CO2 used to synthesize malonyl-CoA from acetyl-CoA appear in palmitate? It is concluded that malonyl-CoA can be synthesized within cardiac myocytes and that the level of this metabolite can be acutely regulated. Malonyl-CoA acts also as an allosteric inhibitor of carnitine palmitoyltransferase-1 (CPT1) … glucose must be converted to acetyl CoA - pyruvate dehydrogenase converts pyruvate to acetyl CoA - only found in mitochondria . Proliferating human cancer cells upregulate this fatty acid synthesis pathway as a strategy for survival. otherwise identical with that employed in palmitate formation of seven malonyl-CoA molecules: 7 Acetyl-CoA + 7CO2 + 7ATP 7 malonyl-CoA The biosynthesis of fatty acids such as palmitate thus Acetyl-CoA carboxylase is activated by phosphorylation and deactivated by dephosphorylation (Shacter et al., 1986). 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