AT, Acyl transferase

Figure 1 Polyketide biosynthesis. Polyketide backbones are formed via condensations from acyl-CoA thioesters of carboxylic acids. The (3-ketone which results from each condensation can undergo a series of reductive steps analogous to fatty acid biosynthesis. However, either none or only some of the reductive activities may occur in a given cycle. This allows PKSs to generate diversity through selection of priming and extender units, variation of the reductive cycle, and stereoselectivity. (ACP, acyl carrier protein AT, acyl transferase KS, ketosynthase DH, dehydratase ER, enoylreductase KR, ketoreductase TE, thioesterase.) The structure depicted in the lower right-hand corner is representative of the possible structural variations that can arise during polyketide biosynthesis.

AT = acyl transferase DH = dehydratase ER = enoyl reductase KR = ketoreductase KS = ketosynthase mAT = methylmalonyl-specific acyl transferase. 

Figure 10.2 The PKS/NRPS biosynthetic paradigm, showing the most common domains and their relative positions within a modular PKS/NRPS enzyme. A = adenylation AT = acyl transferase C = condensation DH = dehydratase Ep = epimerase ER = enoyl reductase KR = ketoreductase KS = ketosynthase MT = methyltransferase PCP = peptidyl carrier protein TE = thioesterase.

Figure 1. Proposed pathway for soraphen A biosynthesis. ACP, acyl carrier protein domain AT, acyl transferase DH, dehydratase ER, enoyl reductase KR, ketoacyl reductase KS, ketoacyl synthase TE, thioesterase. The inactive DH in module 8 is shown as a square. Adapted with permission from reference (9). Copyright 2002 Elsevier Science B. V.

Fig. 5. Predicted domain organization and biosynthetic intermediates of the erythromycin synthase. Each circle represents an enzymatic domain as follows ACP, acyl carrier protein AT, acyl-transferase DH, dehydratase ER, P-ketoacyl-ACP enoyl reductase KR, [3-ketoacyl-ACP reductase KS, p-ketoacyl-ACP synthase TE, thioesterase. Zero indicates dysfunctional domain.

A polyketide chain is formed by the condensation between an acyl thioester intermediate and an acyl carrier protein-bound malonyl or methylmalonyl thioester previously selected and transferred to the acyl carrier protein (AGP) by the AT (acyl-transferase) domain. The mechanism of this KS (ketosynthase)-catalyzed reaction. 

AT = acyl transferase ACP = acyl carrier protein KS = ketosynthase TE = thioesterase KR = (i-ketoacyl reductase ERY = erythromycin RAP = rapamycin... 

Figure 5.24 Schematic representation of the genetic organization of the 40-kb nostopeptohde A biosynthetic gene cluster from Nostoc sp. GSV224. A, adenylation (the predicted activated amino acids are reported as a subscript) C, condensation ACP, acyl carrier protein AT, acyl-transferase KS, p-ketoacyl-ACP synthase PCP, peptidyl carrier protein and TE, thioesterase.

CoA units. In Scheme 11.38, the abbreviations are KS, ketosynthase AT, acyl transferase ACP, acyl carrier protein KR, ketoreductase ER, enoyl reductase DH, dehydratase and TE, thioesterase (to remove the completed chain prior to or concomitant with) cyclization. Finally, as also seen in Scheme 11.38, the formation of erythromycin A requires some small oxidative modifications (and attachment of two sugars at the anomeric carbon) for completion. 

AT = acyl transferase MT = malonyl transferase KS = kefosynfhase ACP = acyl carrier protein... 

AT - acyl transferase KS - P-ketoacyl-synthetase KR - P-ketoreductase DH - dehydratase... 

DHAP-AT dihydroxyacetone phosphate acyl transferase GGF glial growth factor... 

At this point, the acyl-CoA is still in the cytosol of the muscle cell. Entry of the acyl-CoA into the mitochondrial matrix requires two translocase enzymes, carnitine acyl transferase I and carnitine acyl transferase II (CAT I and CAT II), and a carrier molecule called carnitine the carnitine shuttles between the two membranes. The process of transporting fatty acyl-CoA into mitochondria is shown in Figure 7.15. 

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). 

This enzyme [EC 2.3.1.26], also known as sterol O-acyl-transferase, sterol-ester synthase, and cholesterol acyl-transferase, catalyzes the reaction of an acyl-coenzyme A derivative with cholesterol to produce coenzyme A and the cholesterol ester. The animal enzyme is highly specific for transfer of acyl groups having a single cis double bond at C9. 

Further examples of the photolytic generation of thioaldehydes from phenacyl sulfides include the synthesis of 3,6-dihydro-27/-thiopyrans bearing a variety of functions at C-2 of which some are potent acyl-CoA-cholesterol acyl-transferase inhibitors (Equation 135) <1996BMC1493>. 

Answer The transport of fatty acid molecules into mitochondria requires a shuttle system involving a fatty acyl-carnitine intermediate. Fatty acids are first converted to fatty acyl-CoA molecules in the cytosol (by the action of acyl-CoA synthetases) then, at the outer mitochondrial membrane, the fatty acyl group is transferred to carnitine (by the action of carnitine acyl-transferase I). After transport of fatty acyl-carnitine through the inner membrane, the fatty acyl group is transferred to mitochondrial CoA. The cytosolic and mitochondrial pools of CoA are thus kept separate, and no labeled CoA from the cytosolic pool enters the mitochondrion. 

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