KR, Ketoreductase

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)...

L, loading module DH, dehydratase KS, p-ketosynthase KR, ketoreductase MT methyltransferase PS, pyran synthase DHh and KRh are DH and KR-like sequences, together with the FkbH domain, they are involved in the formation of D-lactate starter unit HMG-CS, hydroxy-methyl-glutaryl CoA synthase. Acyl-carrier-protein domains are shown as small filled balls with chain attached by the thiol group. The box shows the HMG-CS pathway for the formation of exocyclic enoate. 

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.

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.

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 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.

Figure 5 Fatty acid biosynthesis catalyzed by fatty acid synthases. The growing acyl chain is tethered to the phosphopantetheinylated ACP domain, which enabies it to undergo cycles of condensation, ketone reduction, dehydration, and enol reduction catalyzed by different domains. AT, acyltransferase ACP, acyi-carrier protein KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyireductase.

Figure 3. Relationship between polyketide and fatty acid biosynthesis. The simplest ( minimaV) PKSs possess ketosynthase activity and produce linear polyketide products. In contrast, FASs also catalyze successive ketoreduction-dehydration-enoyl reduction reactions following each condensation. Diverse PKSs may perform none, part, or all of this reductive sequence. KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyl reductase.

Figure I. Schematic representation of domain architecture in Jungal Type I PKSs based on reported gene sequences. KS. ketoacyl, AT, acyltransferase DH, def dratase KR. ketoreductase ER, enoyl reductase MT, methyltransferase CLC, Claisen-iike cyclase MSAS, methylsalicylic acid synthase THN, tetrahydronaphthalene AF, ST, ( atoxin, sterigmatocystin...

Figure 1. (A) Domain organization of the NcsB naphthoic acid synthase and (B) proposed pathway for biosynthesis of the naphthoic acid intermediate (2) from the acyl CoA substrates by NcsB and its subsequent conversion to 3 by NcsB3 and NcsB 1 and incorporation into neocarzinostatin (I) by NcsB2. ACP, acyl carrier protein AT, acyltransferase DH, dehydratase KR, ketoreductase ...

ACP, acyl carrier protein AT, acyltransferase DH, dehydratase KR, ketoreductase KS, ketoacyl synthase TD, terminal domain that most likely encodes a phosphopantetheinyl transferase. 

FATTY ACID CHAIN EXTENSION CYCLE KS = Ketoacyl Synthase ACP = Acyl Carrier Protein KR = Ketoreductase DHi Dehydratase ER Enoylraductase AT = Acyttransferase TE = TNoesterase... 

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

KS = Ketosynthasa ACP = Acyl carrier protein KR = Ketoreductase AT - Acyl translerase... 

Figure 3.112 Epothilone biosynthetic gene cluster from S. cellulosunu Modular organization of the epottiilone polyketide synthase (PKS) and model for epothilone formation. Abbreviations KS, p-ketoacyl ACP syntfiase KSy, p-ketoacyl ACP synthase containing a tyrosine substitiiion of the active-site cysteine AT, acylti-ansferase DH, dehydratase ER, enoylreductase KR, ketoreductase MT methyltcansferase ACP, acyl carrier protein TE, Ihioesterase C, condensation A, adenylation PCP, peptidyl carrier protein.

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 7.45 Proposed biosynthetic mechanism for zearalenone. KS, ketosynthase MAT, malonyl-CoA ACP acyltransferase DH, dehydratase ER, enoylreductase KR, ketoreductase ACP, acyl carrier protein SAT, N-terminal region starter-unit-ACP transacylase PT, prodnct template TE, C-terminal thioesterase.

Figure 7.S3 Schematic modular organization of candicidin/FR-008 PKS genes fscA, fscB, fscC, fscD, fscE, and fscF. PabAB, 4-amino-4-deoxychorismate (ADC) synthase pabC ADC lyase CoL, CoA hgase ACP, acyl carrier protein KS, ketosynthase AT, acyltransferase mAT, propionate-specific acyltransferase KR, ketoreductase KRi, inactive ketoreductase DH, dehydratase DHi, inactive dehydratase DHs, silent dehydratase ER, enoyl reductase ERi, inactive enoyl reductase.

Figure 7.60 Schematic representation of the organization of the rifamycin B gene cluster and modular organization of the rifamycin PKS leading to proansamycin X. A, T adenylation and thiolation domains of nonribosomal peptide synthetases (NRPS) AGP, acyl carrier protein KS, ketosynthase AT, acyltransferase KR, ketoreductase DH, dehydratase. An asterisk indicates nonfunctional or inactive domains.

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. 

KR = ketoreductase ER = enoyl reductase DH = dehydratase TE = thio erase... 

KS ketosynthase AT acyltransferase KR ketoreductase DH dehydratase ER enoyireductase ACP acyl carrier protein Cy cyclase CM methyltransferase... 

FIGURE 1.2 Chemical logic of polyketide construction leading to variable functionalization of the elongated acyl chain and examples of resulting chemical diversity. ACP, acyl carrier protein DH, dehydratase ER, enoyl reductase KR, ketoreductase KS, ketosynthase MAT, malonyl acyl transferase TE, thioesterase. 

KS ketosynthase AT acetyl/malonyl transferase DH dehydratase ER enoyl reductase KR ketoreductase ACP acyl carrier protein TE thioesterase... 

SCHEME 15.12 Biosynthetic pathway toward antimycins (ANTs), showing modular skeleton assembly, post-tailoring, and preparation of building blocks. KS=ketosynthase, TE=thioesterase, C=condensation, A=adenylation, T=thiolation domain, KR=ketoreductase. 

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