Phosphates activated, chain elongation

The biosynthesis of a variety of biologically active peptides proceeds nucleic acid-free on protein templates (IK Peptide synthetases generally activate an acceptor amino acid by formation of amino-acyl adenylates or phosphates, which will be stabilized in an enzyne-aminoacylation step, similar as in tRNA-aminoacylation. Reaction with a donor peptide, which may be covalently bound, leads to a specific chain elongation. While small peptides like glutathione are formed by "one-step"-synthetases, more complex structures like gramicidin S are produced by multienzvme systems, which may contain multifunctional polypeptides. Characteristic features of such systems are 1.)activation as aminoacyl adenylates, 2.) aminoacylation of enzyme thiol-groups, 3.) covalently bound peptide intermediates and 4.) a specific intrinsic transport mechanism similar to the biosynthesis of fatty acids. 

Some of the concepts most attractive for the simplification of oligonucleotide synthesis and, thus, also for reducing cost and effort of potential large-scale preparations, come from a combination of two of the three operations essential for conventional chain-elongation. Although the combination of protection and activation principles plays a minor role in phosphate-diester and phosphate-triester chemistry, this is the basis of success of the phosphoramidite synthesis (23,24). The relative stability of nucleoside phosphoramidites at room temperature and their fast and efficient activation by tetrazole (23) (see also 25 for mechanistic studies) are essential to today s most utilized process of internucleotide bond formation. 

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). 

The )8-(1 2)- and a-(1 5)-linked arabinose residues are incorporated into the polymer from the activated polyprenyl sugar phosphate 10, which is in turn synthesized from glucose via 5-phosphoribose pyrophosphate (pRpp) [46-48]. Elongation of the polymer chain is believed to involve a family of arabinosyltransferases (AraT s) that recognize both 10 and arabinofuranoside-based acceptors of differing structures (Fig. 5) [18,19,49,50]. In AG biosynthesis, the entire polysaccharide appears to be assembled as a polyprenol diphosphate intermediate, which is transferred to peptidoglycan prior to the addition of the mycolate esters [18]. In LAM biogenesis, the arabinan portion is believed to be synthesized as a polyprenol phosphate that is transferred to lipomannan [51]. 

Abbreviations FASN, fatty acid synthase ACC, acetyl-CoA-carboxylase ACL, ATP-citrate lyase NADPH, nicotinamide adenine dinucleotide phosphate MAT, malonyl acetyl transferases KS, ketoacyl synthase KR, p-ketoacyl reductase DH, p-hydroxyacyl dehydratase ER, enoyl reductase TE, thioesterase ACP, acyl carrier protein VLCFA, very long chain fatty acids ELOVL, elongation of very long chain fatty acids SCDl, stearoyl-CoA desaturase-1 AMPK, AMP-activated kinase ME, malic enzyme FASKOL, liver-specific deletion of FAS PPARa, Peroxisome Proliferator-Activating Receptor alpha HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA SREBP, sterol response element binding protein SIP, site-one protease S2P, site-two... 

The growing fatty acid chain, attached to the fatty acid synthase complex in the cytosol, is elongated by the sequential addition of 2-carbon units provided by malonyl CoA. NADPH, produced by the pentose phosphate pathway and the malic enzyme, provides reducing equivalents When the growing fatty acid chain is 16 carbons in length, it is released as palmitate After activation to a CoA derivative, palmitate can be elongated and desaturated to produce a series of fatty acids. 

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