TE, Thioesterase

Figure 11.2 Biosynthesis of the nine-membered enediynes. Members of this family share a common biosynthetic pathway for the enediyne core intermediate. Domains are shown in circles with abbreviations (KS, ketosynthase AT, acyltransferase KR, ketoreductase DH, dehydratase TE, thioesterase ACP, acyl carrier protein PPT, phosphopantetheine transferase)...

Figure 11.5 Amino acid building blocks are incorporated into daptomycin backbone successively by NRPS subunits DptA, DptBC and DptD (a). Structural diversity of daptomycin peptide core can be obtained by genetic modifications of dpt gene cluster (b). C, condensation domain A, adenylation domain PCP, peptidyl carrier protein E, epimerase TE, thioesterase domain... 

Scheme 23 Example of an acyl carrier protein (ACP in red) in a type I FAS. The palmitic acid is depicted as a representative fatty acid. During its biosynthesis, the ACP (red) interacts iteratively with each domain (DH, dehydrogenase ER, enoyl reductase KR, ketoreductase KS, ketosynthase TE, thioesterase) until the palmitic acid has reached its proper length.

A adenylation domain PCP peptidyl carrier protein domain C condensation domain E epimerization domain (Val module only) TE thioesterase domain... 

ACP acyl carrier protein DH dehydratase ER enoylreductase KR P-ketoacylreductase KS P-ketoacylsynthase MAT malonyl/acetyltransferase TE thioesterase... 

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

ACP acyl carrier protein AT acyltransferase DH dehydratase ER enoyl reductase KR p-ketoacyl reductase KS p-ketoacyl synthase TE thioesterase... 

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.

Figure 5 Domain organization of the erythromycin polyketide synthase. Putative domains are represented as circles and the structural residues are ignored. Each module incorporates the essential KS, AT, and ACP domains, while all but one include optional reductive activities. AT, acyltransferase ACP, acyl carrier protein KS, (3-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydratase ER, enoyl reductase TE, thioesterase.

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 6 HMGS containing biosynthetic pathways. Portions of the PKS and PKS/NRPS pathways where the HMGS and related enzymes are located. Abbreviations A - Adenylation, AGP - acyl carrier protein, AT - acyltransferase, Cy - cyciization, DH - dehydratase, ER - enoyl reductase, GNAT -CCN5-related N-acetyltransferase, KS - ketosynthase, KR - ketoreductase, MT - methyltransferase. Ox - Oxidase, Oxy - Oxygenase, PGP - peptide carrier protein, PhyH - phytanoyl-CoA dioxygenase, PS - pyrone synthase, TE - thioesterase, - unknown function, - inactive domain.

KS = /3-Ketoacyl synthase MT = malonyl transacylase AT = acetyl transacylase DH = dehydratase ER = enoyl reductase KR = /3-ketoacyl reductase ACP = acyl carrier site TE = thioesterase. [Reproduced with permission from S. J. Wakil, J. K. Stoops, and V. C. Joshi, Fatty acid synthesis and its regulation. Annu. Rev. Biochem. 52, 537 (1983). 1983 by Annual Reviews Inc.]... 

ACP = acyl carrier protein KS = p-ketoacyl synthase KR = p-ketoacyl reductase ER = enoyl reductase DH = dehydratase 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.

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... 

Fig. 3. Generic reaction sequence for the FASs. ACP, acyl carrier protein AT, acetyltransferase MT, malonyl transferase KS, P-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydrase ER, enoyl reductase TE, thioesterase FT, palmitoyl transferase. In the animal FAS the acetyl and malonyl loading reactions are catalyzed by the same acyl transferase and the chain-termination reaction is catalyzed by a thioesterase. In the fungal FAS, the malonyl loading and palmitoyl unloading reactions are catalyzed by the same acyl transferase. Stereochemical analyses in the laboratories of Comforth and Hammes established that in both animal and fungal FASs the KS-catalyzed condensation reaction proceeds with inversion of configuration at the malonyl C2 position, followed by KR-catalyzed reduction of the 3-keto moiety to the 3R alcohol by transfer of the pro-4S hydride from NADPH, and DH-catalyzed dehydration to a trans-enoyl moiety by the syn elimination of the 2S hydrogen and the 3/f hydroxyl as water. However, the stereochemistry of the final reduction reaction catalyzed by ER domain proceeds with different stereochemistry. The animal FAS transfers the pro-4R hydride of NADPH to the pro-3/f position with simultaneous addition of a solvent proton to the pro-2S position, whereas the fungal FAS takes the pro-4S hydride of NADPH into the pro-3S position and the solvent proton is incorporated at the pro-25 position.

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.

KR - ketoreductase, ER - enoyl reductase, DH - dehydratase, ACP - acyl carrier protein, TE - thioesterase. 

Figure 11.2 A comparative picture of the fatty acid synthetase (FAS) systems in yeast, animal, bacterial and plant cells. fi-KS, -ketoacyl AGP synthetase P-KR, A-ketoacyl AGP reductase DH, -OH acyl-AGP dehydrase ER, enoyl AGP reductase AT, acetyl transacylase MT, malonyl transacylase TE, thioesterase AGP, acyl carrier protein. See Shimakata and Stumpf (19S2a,b) and Wakil etal, (1983) for details.

The hybrid PKS consists of the loading module, the first extension module, and the KS2 domain derived from the second extension module of the erythromycin PKS this is fused at the ATI 1 domain of the rapamycin PKS modules 11 and 12. The terminal TE (thioesterase) domain of the erythromycin PKS is then fused to the rapamycin module 12 ACP domain (Figure 2.16) [32]. 

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

Figure 3 9 Biosynthesis of natural and unnatural cyclomarin and cyclomarazine analogs. Supplementing cultures of the S. arenicola cymD mutant with tryptophan analogs yields known and novel cyclomarins and cyclomarazines. Abbreviations A, adenylation domain C, condensation domain M1-M7, modules 1-7 MT, methyltransferase T, thiolation domain and TE, thioesterase.

Figure 4.16 Schematic representation of the genetic organization of the nocardicin biosynthetic gene clnster from N. uniformis and modular organization of the NRPS genes nocA and nocB. A, adenylation C, condensation E, epimeiization T, thiolation and TE, thioesterase.

Figure 4.39 Organization and presumed action of the four NRPS modules in the cpbl and cpbK genes involved in the later steps of cephabacin F3 biosynthesis. C, condensation domain A, adenylation domain T, thiolation domain AT, acyltransferase KS, ketosynthase KR, ketoreductase ACP, acyl carrier protein and TE, thioesterase.

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.

Figure 7.38 Schematic representation of the erythromycin gene cluster in Saccharopolyspora erythraea and proposed pathway to 6-deoxyerythronolide B. AT, acyltransferase ACP acyl carrier protein KS, 3-ketoacylsynthase KR, 3-ketoacylreductase ER, enoyireductase DH, dehydratase TE, thioesterase.

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