Fatty acids acyl phosphates

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). 

Lipid A of Salmonella contains glucosamine, fatty acid and phosphate, with variable amounts of phosphoethanolamine and 4-amino-L-arabinose. Two molecules of glucosamine are pi,6-linked to each other and are very heavily substituted by fatty acyl residues. There are four molecules of 3-hydroxymyristate, seven molecules of long-chain fatty acid and three molecules of non-hydroxylated fatty acid per disaccharide, producing an extremely hydrophobic structure. The first glucosamine residue is attached to phosphate at C-1 and, thence, to ethanolamine and the second is substituted at C-4 by phosphate and, thence, can be attached to 4-amino-L-arabinose. For reviews of this structure see Westphal et al (1981) and Reitschel et al. (1981). It should be noted that lipid A is microheterogeneous. 

The free fatty acids formed by lipolysis can be reconverted in the tissue to acyl-CoA by acyl-CoA synthetase and reesterified with glycerol 3-phosphate to form triacylglycerol. Thus, there is a continuous cycle of lipolysis and reesterification within the tissue. However, when the rate of reesterification is not sufficient to match the rate of lipolysis, free fatty acids accumulate and diffuse into the plasma, where they bind to albumin and raise the concentration of plasma free fatty acids. 

CoA. Two high-energy phosphate equivalents are required to activate fatty acids to the acyl-CoA. 

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. 

As these results and Fig. 2 show, three structural components may be defined in lipid A (/) the lipid A backbone consisting of a pyranosidic HexN disaccharide and phosphate groups, (ii) substituents of the backbone phosphate residues (polar head groups), and (iii) fatty acids. Therefore, lipid A of different bacteria may be classified according to the nature of the backbone constituents (GlcpN or GlcpN3N), the type and nature of the polar head groups, and features of the acylation pattern. In a few instances, other backbone substituents have been encountered. These will be described later in conjunction with individual lipid A forms. 

Triglycerides, the storage form of fatty acids, are formed by attaching three fatty adds (as fetty acyl CoA) to glycerol. Triglyceride formation from fatty acids and glycerol 3-phosphate occurs primarily in liver and adipose tissue. 

Figure 11.4 Condensation, dehydration and reduction reactions in fatty add synthesis. These reactions constitute the major components of the pathway of fatty acid synthesis and are all catalysed by fatty acid synthase. The reduction reactions, indicated by addition of 2H in the diagram, involve the conversion of NADPH to NADP . (The re-conversion of NADP back to NADPH occurs in the pentose phosphate pathway.) The condensation reaction results in an increase in size of acyl-ACP by two carbon units in each step. The two carbons for each extension are each provided by malonyl-CoA. ACP - acyl carrier protein.

The initial acylation at the 1-position of glycerol 3-phosphate is catalysed by glycerol 3-phosphate acyl-transferase-1, abbreviated to GPAT-1. This enzyme is specific for a saturated fatty acid (in the acyl form). 

The second acylation at position 2 is catalysed by GPAT-2, which is specific for a fatty acid with one or two double bonds. This produces phosphatidic acid, for which the phosphate must be removed prior to the final acylation. 

Figure 11.7 Synthesis of triaq/lglyceroL The precursors are glycerol 3-phosphate and long-chain acyl-CoA. R, is a saturated fatty acid, R2 is an unsaturated fatty acid (one or two doubte bonds) and R3 is either saturated or unsaturated. The activity of GPAT-1 regulates triacylglycerol synthesis. In all reactions involving RCO.SCoA, the CoASH is released but is not shown in this diagram. P,- - phosphate.

Acylation describes the process by which a fatty acid reacts with another molecule (e.g. glycerol phosphate) or with a protein, to facilitate attachment of the protein to a membrane. 

Further examples of acylphosphates are found in fatty acyl-AMPs (see Section 15.4.1) and aminacyl-AMPs (see Section 13.5), activated intermediates in the metabolism of fatty acids and formation of peptides respectively. Each of these is attacked on the C=0 by an appropriate S or O nucleophile, displacing the phosphate derivative AMP. 

The fatty acid is initially converted into an acyl-AMP derivative by attack of the carboxylate as a nucleophile onto the P=0 system of ATP, with loss of diphosphate as a leaving group. This reaction is far from favourable, and the equilibrium is disturbed by subsequent pyrophosphatase-catalysed hydrolysis of diphosphate into two molecules of phosphate. 

Esterification of glycerol 3-phosphate with a long-chain fatty acid produces a strongly amphipathic lysophosphatidate (enzyme glycerol-3-phosphate acyltransferase 2.3.1.15). In this reaction, an acyl residue is transferred from the activated precursor acyl-CoA to the hydroxy group at C-1. 

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