AcpS, Acyl carrier protein synthase

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.

MALONYL-CoA ACP-TRANSACYASE Acyl carrier protein synthase,... 

Figure 3.8 One complete cycle and the first step in the next cycle of the events during the synthesis of fatty acids. ACP = acyl carrier protein, a complex of six enzymes i.e. acetyl CoA-ACP transacetylase (AT) malonyl CoA-ACP transferase (MT) /3-keto-ACP synthase (KS) /J-ketoacyl-ACP reductase (KR) / - hydroxyacyl-ACP-dehydrase (HD) enoyl-ACP reductase (ER).

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 3 The fatty acid biosynthetic cycle (ACP, acyl carrier protein KS, P-ketoacyl synthase KR, P-ketoacyl reductase DH, dehydratase ER, enoyl reductase TE, thioes-terase).

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 10.1 Domain and modular structure of 6-deoxyerythronolide B synthase (DEBS), the model modular PKS. ACP = acyl carrier protein ...

FATTY ACID CHAIN EXTENSION CYCLE KS Ketoacyl Synthase ACP = Acyl Carrier Protein KR Ketoreductaso DH =... 

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

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. 

F/gwre J. Installation of alkyl branches into polyketides by (A) and (B) noniterative type I PKSs or (C) and (D) AT4ess PKSs. ( ), methyl group of S-adenosylmethionine origin ACP, acyl carrier protein AT, malonyl CoA specific acyltransferase ATmm methylmalonyl CoA-specific acyltransferase Tfno, methoxymalonyl ACP-specific acyltransferase KS, ketoacyl synthase MT, methyltransferase SAM, S-adenosylmethionine. 

The first step in de novo fatty acid synthesis is the production of malonyl-CoA from acetyl-CoA and bicarbonate. This committed step is catalyzed by acetyl-CoA carboxylase present in the cytoplasm of liver cells and adipocytes. After replacement of the CoA residue in acetyl-CoA by ACP (acyl carrier protein), malonyl-ACP is used to convert acetyl-ACP to butyryl-ACP by the fatty acid synthase complex. In this multistep reaction, NADPH is used as donor of hydrogen atoms and CO2 is produced. Butyryl-ACP is subsequently elongated to hexanoyl-ACP by a similar process in which malonyl-ACP serves as donor of two carbon atoms required for lengthening of the growing acyl chain. This process is repeated until palmitic acid... 

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.

Scheme 13. Proposed mode of action of ery-thromycin-PKS. KS = ketoacyl synthase KR = keto reductase DH = deydratase ER = enol reductase ACP = acyl carrier protein CoA=coenzyme A.

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 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.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.

Synthetic apo-ACP protein, a polypeptide representing amino acids 2-74 of the E. coli protein, functions as substrate for the holo-acyl-carrier protein synthase (EC 2.7.S.7) the product has the same biological activity as natural holo-ACP. 

Proposed structure of the dimer of type I fatty acid synthase (based on studies of the chicken liver enzyme). ACP = acyl carrier protein, KR = p-ketoacyl reductase, MT = malonyl transacylase. 

AT = acyl transferase (from acetylCoA to the PKS) ACP = acyl carrier protein KS = keto synthase... 

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