Fatty acid synthase reactions

The first domain of one subunit of the fatty acid synthase interacts with the second and third domains of the other subunit that is, the subunits are arranged in a head-to-tail fashion (Figure 25.9). The first step in the fatty acid synthase reaction is the formation of an acetyl-O-enzyme intermediate between the acetyl group of an acetyl-CoA and an active-site serine of the acetyl trails-... 

The Fatty Acid Synthase Reactions Are Repeated to Form Palmitate... 

Six more molecules of malonyl-ACP react successively at the carboxyl end of the growing fatty acid chain to form palmitoyl-ACP—the end product of the fatty acid synthase reaction. Free palmitate is released by hydrolysis. 

Fig. 2. Various reactions leading to acyl-CoA. The pyruvate dehydrogenase reaction is in fact a sequence of five reactions catalyzed by a three enzyrmes complex. It is the major pathway producing acetyl-CoA, a key molecule in many important metabolic pathways such as the oxidative degradation of glucides (citric acid cycle, also known as Krebs cycle ). Acetyl-CoA is also the starting point for the symthesis of fatty acids, through the fatty acid synthase reaction, which increases the length of the starting fatty acid (R) by two carbon atoms. Most of the other acyl-CoAs are obtained through the acyl-CoA ligase reaction.

In animals, the enzymes of fatty acid synthesis are components of one long polypeptide chain, the fatty acid synthase, whereas no similar association exists for the degradative enzymes. (Plants and bacteria employ separate enzymes to carry out the biosynthetic reactions.)... 

Rittenberg and Bloch showed in the late 1940s that acetate units are the building blocks of fatty acids. Their work, together with the discovery by Salih Wakil that bicarbonate is required for fatty acid biosynthesis, eventually made clear that this pathway involves synthesis of malonyl-CoA. The carboxylation of acetyl-CoA to form malonyl-CoA is essentially irreversible and is the committed step in the synthesis of fatty acids (Figure 25.2). The reaction is catalyzed by acetyl-CoA carboxylase, which contains a biotin prosthetic group. This carboxylase is the only enzyme of fatty acid synthesis in animals that is not part of the multienzyme complex called fatty acid synthase. 

The enzymes that catalyze formation of acetyl-ACP and malonyl-ACP and the subsequent reactions of fatty acid synthesis are organized quite differently in different organisms. We first discuss fatty acid biosynthesis in bacteria and plants, where the various reactions are catalyzed by separate, independent proteins. Then we discuss the animal version of fatty acid biosynthesis, which involves a single multienzyme complex called fatty acid synthase. 

As seen already, palmitate is the primary product of the fatty acid synthase. Cells synthesize many other fatty acids. Shorter chains are easily made if the chain is released before reaching 16 carbons in length. Longer chains are made through special elongation reactions, which occur both in the mitochondria and at the surface of the endoplasmic reticulum. The ER reactions are actually quite similar to those we have just discussed addition of two-carbon units... 

Figure 21-2. Fatty acid synthase multienzyme complex. The complex is a dimer of two identical polypeptide monomers, 1 and 2, each consisting of seven enzyme activities and the acyl carrier protein (ACP). (Cys— SH, cysteine thiol.) The— SH of the 4 -phosphopantetheine of one monomer is in close proximity to the— SH of the cysteine residue of the ketoacyl synthase of the other monomer, suggesting a "head-to-tail" arrangement of the two monomers. Though each monomer contains all the partial activities of the reaction sequence, the actual functional unit consists of one-half of one monomer interacting with the complementary half of the other. Thus, two acyl chains are produced simultaneously. The sequence of the enzymes in each monomer is based on Wakil.

From here it s just the reaction catalyzed by fatty acid synthase. 

The reactions of fatty acid synthesis all occur on one enzyme—fatty acid synthase.1 This enzyme has multiple catalytic activities on one polypeptide chain. The intermediates of the reaction are not released until... 

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 ... 

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.

All the reactions in the pathway take place on a multienzyme complex, fatty acid synthase, which has seven catalytic activities or functional domains. Details of the individual reactions are presented in Appendix 11.1. 

Figure 11.5 Reactions of the fatty acid synthase complex. A single multi-subunit enzyme is responsible for the conversion of acetyl-CoA to palmitate. The subunits in the enzyme are (i) acetyltransferase, (ii) malonyltransferase, (iii) oxoacyl synthase, (iv) oxoacyl reductase, (v) hydroxyacyl dehydratase, (vi) enoyl reductase. Finally, a separate enzyme, thioester hydrolase, hydrolyses palmitoyl-CoA to produce palmitate (vii).

Fatty acid synthesis is catalysed in animals by the enzyme fatty acid synthase, which is a multifunctional protein containing all of the catalytic activities required. Bearing in mind the necessity to provide a specific binding site for the various substrates involved, and then the fairly complex sequence of reactions carried out, it raises the question of just how it is possible for this process to be achieved at the enzymic level. Nature has devised an elaborate but satisfyingly simple answer to this problem. 

The first step is carboxylation of acetyl CoA to malonyl CoA. This reaction is catalyzed by acetyl-CoA carboxylase [5], which is the key enzyme in fatty acid biosynthesis. Synthesis into fatty acids is carried out by fatty acid synthase [6]. This multifunctional enzyme (see p. 168) starts with one molecule of ace-tyl-CoA and elongates it by adding malonyl groups in seven reaction cycles until palmi-tate is reached. One CO2 molecule is released in each reaction cycle. The fatty acid therefore grows by two carbon units each time. NADPH+H is used as the reducing agent and is derived either from the pentose phosphate pathway (see p. 152) or from isocitrate dehydrogenase and malic enzyme reactions. 

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). 

Fatty acid synthase in vertebrates consists of two identical peptide chains—i. e., it is a homodimer. Each of the two peptide chains, which are shown here as hemispheres, catalyzes all seven of the partial reactions required to synthesize palmitate. The spatial compression of several successive reactions into a single multifunctional enzyme has advantages in comparison with separate enzymes. Competing reactions are prevented, the individual reactions proceed in a coordinated way as if on a production line, and due to low diffusion losses they are particularly ef dent. 

Each subunit of the enzyme binds acetyl residues as thioesters at two different SH groups at one peripheral cysteine residue (CysSH) and one central 4-phosphopante-theine group (Pan-SH). Pan-SH, which is very similar to coenzyme A (see p. 12), is covalently bound to a protein segment of the synthase known as the acyl-carrier protein (ACP). This part functions like a long arm that passes the substrate from one reaction center to the next. The two subunits of fatty acid synthase cooperate in this process the enzyme is therefore only capable of functioning as a dimer. 

All the reactions in the synthetic process are catalyzed by a multienzyme complex, fatty acid synthase. Although the details of enzyme structure differ in prokaryotes such as Escherichia coli and in eukaryotes, the four-step process of fatty acid synthesis is the same in all organisms. We first describe the process as it occurs in A1, coli, then consider differences in enzyme structure in other organisms. 

The remaining series of reactions of fatty acid synthesis in eukary-l otes is catalyzed by the multifunctional, dimeric enzyme, fatty acid synthase. Each fatty acid synthase monomer is a multicatalytic polypeptide with seven different enzymic activities plus a domain that covalently binds a molecule of 4 -phosphopantetheine. [Note 4-Phosphopantetheine, a derivative of the vitamin pantothenic add (see p. 379), carries acetyl and acyl units on its terminal thiol (-SH)j group during fatty acid synthesis. It also is a component of 00-enzyme A.] In prokaryotes, fatty acid synthase is a multienzyme complex, and the 4 -phosphopantetheine domain is a separate protein, referred to as the acyl carrier protein (ACP). ACP is used below to refer to the phosphopantetheine-binding domain of the eukaryotic fatty acid synthase molecule. The reaction numbers in1 brackets below refer to Figure 16.9. [Note The enzyme activities listed are actually separate catalytic domains present in each mulf-1 catalytic fatty acid synthase monomer.]... 

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