In vitro kinetic study of the squalestatin tetraketide synthase dehydratase reveals the stereochemical course of a fungal highly reducing polyketide synthase

Abstract

The substrate selectivity of the isolated dehydratase (DH) domain of a fungal highly-reducing polyketide synthase is closely related to that of mammalian fatty acid synthase.

Identification and Heterologous Production of a Benzoyl-Primed Tricarboxylic Acid Polyketide Intermediate from the Zaragozic Acid A Biosynthetic Pathway

“…Labeling studies have shown the tricarboxylic acid core is partially-derived from oxaloacetate, an intermediate found in the citric acid cycle. 11 Cox et al have shown the tetraketide arm (left in Figure 1) in 1 is synthesized by a HRPKS 12 and enzymatically esterified to the core in the last biosynthetic step. 13 However, formation of the other polyketide arm of 1 is unresolved.…”

“…Clz2 is highly homologous to the previously identified squalestatin tetraketide synthase. 12, 15 Also present is the acyltransferase Clz6 that catalyzes transferring of tetraketide product to the hydroxyl group in the tricarboxylic acid core. 13 Therefore, we designated the clz cluster to be responsible for 1 in C. lunata .…”

Strobilurin biosynthesis in Basidiomycete fungi

“…Xie and Cane recently showed that in the cases of bongkrekic acid and oxazolomycin, produced by bacterial trans -AT PKS, a KR sets up a β-alcohol anti to an α-proton and the subsequent syn dehydration gives the Z -olefin directly 40 . The only KR/DH pair from a fungal hr-PKS investigated in vitro is from the SQTKS and this has a KR, which reduces to give the opposite alcohol diastereomer and the subsequent syn DH yields the E -olefin 41 . The strobilurin PKS is unique in being an iterative type I system that creates the Z -olefin.…”

Reengineering the programming of a functional domain of an iterative highly reducing polyketide synthase

“…It shows very high stereoselectivity for 2R-3R-substrates, but low chain-length selectivity being able to dehydrate di, tri and tetraketides. 12,13 In both cases, the stereoselectivities of the DH and ER domains (and by inference the KR domain) of SQTKS have been shown to be identical to that of vFAS. Vederas and coworkers have conducted parallel experiments with isolated KR and C-MeT domains from the lovastatin nonaketide synthase (LNKS) 13 and shown that these two domains also display different levels of selectivity.…”