Acyl-CoA synthase

Fatty-acid synthase (acyl-CoA malonyl-CoA C-acyltransferase, EC 2.3.1.85) is a multifunctional transferase that also has the capacity to hydrolyze thiolesters. The role of its thiolesterase domain is to terminate the growth of fatty acids by hydrolyzing acyl-CoA intermediates [131]. 

Ligases Ligase, synthase, acyl-CoA Used for polymer... 

FIGURE 25.7 The pathway of palmhate synthesis from acetyl-CoA and malonyl-CoA. Acetyl and malonyl building blocks are introduced as acyl carrier protein conjugates. Decarboxylation drives the /3-ketoacyl-ACP synthase and results in the addition of two-carbon units to the growing chain. Concentrations of free fatty acids are extremely low in most cells, and newly synthesized fatty acids exist primarily as acyl-CoA esters. 

Long-chain fatty acids (e.g., palmitate Cig) diffuse through pores in the outer mitochondrial membrane, and then form long-chain acyl-CoA esters catalyzed reversibly by palmitoyl-CoA synthase (assumed to be on the inner face of the outer membrane). 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

The biosynthesis of polyketides (including chain initiation, elongation, and termination processes) is catalyzed by large multi-enzyme complexes called polyketide synthases (PKSs). The polyketides are synthesized from starter units such as acetyl-CoA, propionyl-CoA, and other acyl-CoA units. Extender units such as malonyl-CoA and methylmalonyl-CoA are repetitively added via a decarboxylative process to a growing carbon chain. Ultimately, the polyketide chain is released from the PKS by cleavage of the thioester, usually accompanied by chain cyclization [49]. 

L, loading module DH, dehydratase KS, p-ketosynthase KR, ketoreductase MT methyltransferase PS, pyran synthase DHh and KRh are DH and KR-like sequences, together with the FkbH domain, they are involved in the formation of D-lactate starter unit HMG-CS, hydroxy-methyl-glutaryl CoA synthase. Acyl-carrier-protein domains are shown as small filled balls with chain attached by the thiol group. The box shows the HMG-CS pathway for the formation of exocyclic enoate. 

Once fatty acids have been made 16 carbons long, they can be lengthened by adding 2 carbon atoms at a time with malonyl-CoA in a reaction that looks a lot like the first step of fatty acid synthesis. However, the elongation reaction is carried out on the fatty acyl-CoA and by an enzyme that is different from fatty acid synthase.4 ... 

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

YPClp exhibits reverse activity in cells and in vitro. This activity is not inhibited by FBI and is fatty acyl-CoA independent, suggesting that the reverse activity of YPClp is distinct from the FBI inhibitable ceramide synthase activity which uses fatty acyl-CoA as substrate, but not a free fatty... 

Pantothenic acid CoA i Fatty acid synthase Fatty acyl CoA synthetase Pyruvate dehydrogenase ci-Ketoglutarate dehydrogenase Fatty acid metabolism PDH TCA cycle Rare... 

The elongation of the fatty acid by fatty acid synthase concludes at Cie, and the product, palmitate (16 0), is released. Unsaturated fatty acids and long-chain fatty acids can arise from palmitate in subsequent reactions. Fats are finally synthesized from activated fatty acids (acyl CoA) and glycerol 3-phosphate (see p. 170). To supply peripheral tissues, fats are packed by the hepatocytes into lipoprotein complexes of the VLDL type and released into the blood in this form (see p. 278). 

Citrate synthase catalyzes the aldol reaction between acetyl-CoA and oxaloace-tate. The acyl-CoA Hnk is then cleaved by hydrolysis, releasing a molecule of citrate and free CoA. 

Polyhydroxyalkanoate synthase (systematic name acyl-CoA 3-hydroxybutyrate 0-acyltransferase EC 2.3.1. class) is responsible for the polymerizations of PHAs in vivo because it catalyzes the stereoselective conversion of (/ )-3-hydroxyacyl-CoA substrates to PHAs with the concomitant release of CoA (see Fig. 2) [3]. 

Scheme 23.4 Production of methylketones from fatty acids by Penicillium roqueforti. 1 ATP-de-pendent acylcoenzyme A (acyl-CoA) synthase 2 flavin adenine dinucleotidedependent acyl-CoA dehydrogenase 3 enoyl-CoA hydratase 4 NAD-dependent 3-hydroxyacyl-CoA dehydrogenase 5 3-oxoacyl-CoA thiolase 6 3-oxoacyl-CoA thiolester hydrolase and 3-oxoacid decarboxylase. (Adapted from [46])...

Table 2.1.9 Changes of blood amino acids in various primary inherited defects and as a result of secondary changes. ASA Argininosuccinic acid, CPS carbamoyl phosphate synthase, LPI Lysinuric protein intolerance, MAD multiple acyl-CoA dehydrogenation, MSUD maple syrup urine disease, NAGS N-acetylglutamate synthase, NKH nonketotic hyperglycinemia, NTBC 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione, OCT Ornithine carbamoyltransferase,...

D-bifunctional protein deficiency [5], 2-methyl acyl-CoA racemase (AMACR) deficiency [3] and sterol carrier protein (SCP-x) deficiency [6], the disorders of etherphospholipid biosynthesis (dihydroxyacetone phosphate acyltransferase and alkyl- dihydroxyacetone phosphate synthase deficiency) [2], the disorders of phytanic acid alpha-oxidation (Refsum disease) [15], and the disorders of glyoxylate detoxification with hyperoxaluria type 1 as caused by alanine glyoxylate aminotransferase deficiency as a sole representative. 

The condensation of acetyl CoA and oxaloacetate to form citrate is catalyzed by citrate synthase (Figure 9.5). This aldol condensation has an equilibrium far in the direction of citrate synthesis. Citrate synthase is allosterically activated by Ca2+ and ADP, and inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives (see Figure 9.9). However, the primary mode of regulation is also deter mined by the availability of its substrates, acetyl CoA and oxaloac etate. [Note Citrate, in addition to being an intermediate in the TCA cycle, provides a source of acetyl CoA for the cytosolic synthesis of... 

Pantothenic acid is a component of coenzyme A, which functions in the transfer of acyl groups (Figure 28.17). Coenzyme A contains a thiol group that carries acyl compounds as activated thiol esters. Examples of such structures are succinyl CoA, fatty acyl CoA, and acetyl CoA. Pantothenic acid is also a component of fatty acid synthase (see p. 182). Eggs, liver, and yeast are the most important sources of pan tothenic acid, although the vitamin is widely distributed. Pantothenic acid deficiency is not well characterized in humans, and no RDA has been established. 

Citrate is synthesized from oxaloacetate (OAA) and acetyl CoA by citrate synthase. This enzyme is allosterically activated by ADP, and inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives. Citrate is isomerized to isocitrate by aconitase, an enzyme that is targeted by the rat poison, fluoroacetate. 

In higher animals as well as in My cobacterium,207 yeast,208 and Euglena, the fatty acid synthase consists of only one or two multifunctional proteins. The synthase from animal tissues has seven catalytic activities in a single 263-kDa 2500-residue protein 209 The protein consists of a series of domains that contain the various catalytic activities needed for the entire synthetic sequence. One domain contains an ACP-like site with a bound 4 -phosphopantetheine as well as a cysteine side chain in the second acylation site. This synthase produces free fatty acids, principally the C16 palmitate. The final step is cleavage of the acyl-CoA by a thioesterase, one of the seven enzymatic activities of the synthase. See Chapter 21 for further discussion. 

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