The architectures of iterative type I PKS and FAS

Abstract

Covering: up to mid of 2018 Type I fatty acid synthases (FASs) are giant multienzymes catalyzing all steps of the biosynthesis of fatty acids from acetyl- and malonyl-CoA by iterative precursor extension. Two strikingly different architectures of FAS evolved in yeast (as well as in other fungi and some bacteria) and metazoans. Yeast-type FAS (yFAS) assembles into a barrel-shaped structure of more than 2 MDa molecular weight. Catalytic domains of yFAS are embedded in an extensive scaffolding matrix and arranged around two enclosed reaction chambers. Metazoan FAS (mFAS) is a 540 kDa X-shaped dimer, with lateral reaction clefts, minimal scaffolding and pronounced conformational variability. All naturally occurring yFAS are strictly specialized for the production of saturated fatty acids. The yFAS architecture is not used for the biosynthesis of any other secondary metabolite. On the contrary, mFAS is related at the domain organization level to major classes of polyketide synthases (PKSs). PKSs produce a variety of complex and potent secondary metabolites; they either act iteratively (iPKS), or are linked via directed substrate transfer into modular assembly lines (modPKSs). Here, we review the architectures of yFAS, mFAS, and iPKSs. We rationalize the evolution of the yFAS assembly, and provide examples for re-engineering of yFAS. Recent studies have provided novel insights into the organization of iPKS. A hybrid crystallographic model of a mycocerosic acid synthase-like Pks5 yielded a comprehensive visualization of the organization and dynamics of fully-reducing iPKS. Deconstruction experiments, structural and functional studies of specialized enzymatic domains, such as the product template (PT) and the starter-unit acyltransferase (SAT) domain have revealed functional principles of non-reducing iterative PKS (NR-PKSs). Most recently, a six-domain loading region of an NR-PKS has been visualized at high-resolution together with cryo-EM studies of a trapped loading intermediate. Altogether, these data reveal the related, yet divergent architectures of mFAS, iPKS and also modPKSs. The new insights highlight extensive dynamics, and conformational coupling as key features of mFAS and iPKS and are an important step towards collection of a comprehensive series of snapshots of PKS action.

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

“…Bacteria and plants perform fatty acid biosynthesis with separate, monofunctional enzymes in a dissociated fatty acid biosynthesis system, referred to as a type II FAS system . In contrast, in eukaryotes and particular bacteria of the subgroup of Corynebacterineae [ Corynebacteria , Mycobacteria , and Nocardia (CMN bacteria)], fatty acid biosynthesis occurs in large multifunctional FASs, termed type I FASs, in which all the required enzymatic activities are integrated into multidomain complexes . De novo fatty acid biosynthesis resembling that catalyzed by bacterial type II FASs is also found in mitochondria…”

“…Whereas fungal and CMN‐bacterial FASs form large barrel‐shaped complexes (about 2.6 MDa) with enclosed reaction chambers, animal FASs are dimers of multidomain polypeptides in an overall open structural arrangement. An exhaustive review on the three‐dimensional structures of type I FASs was recently published elsewhere …”

“…Remarkable sequence and functional similarity can also be found for animal FASs and polyketide synthases (PKSs) . A fully methylating iterative PKS was identified as a common evolutionary ancestor, underlined by the non‐functional evolutionary relic of a methyltransferase (MT) domain—that only fulfills structural tasks—in the animal FAS scaffold …”

Expanding the Chemical Palette of Industrial Microbes: Metabolic Engineering for Type III PKS‐Derived Polyketides

“…Polyketides are an extremely diverse class of secondary metabolites natively produced by a host of microbial organisms and plants and employed for a variety of purposes including defense, pigmentation, and communication . On a biochemical basis, polyketides are formed by polyketide synthases (PKSs) that catalyze the iterative condensation of CoA precursors into a polyketide chain, which is then cyclized . However, these PKSs vary greatly in structure and are typically classified as one of three different types.…”

“…However, these PKSs vary greatly in structure and are typically classified as one of three different types. Type I and type II PKSs comprise large protein assemblies with many specialized subunits . In contrast, type III PKSs are small, homodimeric enzymes with active sites that perform both chain extension and cyclization .…”