Microbial Type I Fatty Acid Synthases (FAS): Major Players in a Network of Cellular FAS Systems

Abstract

The present review focuses on microbial type I fatty acid synthases (FASs), demonstrating their structural and functional diversity. Depending on their origin and biochemical function, multifunctional type I FAS proteins form dimers or hexamers with characteristic organization of their catalytic domains. A single polypeptide may contain one or more sets of the eight FAS component functions. Alternatively, these functions may split up into two different and mutually complementing subunits. Targeted inactivation of the individual yeast FAS acylation sites allowed us to define their roles during the overall catalytic process. In particular, their pronounced negative cooperativity is presumed to coordinate the FAS initiation and chain elongation reactions. Expression of the unlinked genes, FAS1 and FAS2, is in part constitutive and in part subject to repression by the phospholipid precursors inositol and choline. The interplay of the involved regulatory proteins, Rap1, Reb1, Abf1, Ino2/Ino4, Opi1, Sin3 and TFIIB, has been elucidated in considerable detail. Balanced levels of subunits α and β are ensured by an autoregulatory effect of FAS1 on FAS2 expression and by posttranslational degradation of excess FAS subunits. The functional specificity of type I FAS multienzymes usually requires the presence of multiple FAS systems within the same cell. De novo synthesis of long-chain fatty acids, mitochondrial fatty acid synthesis, acylation of certain secondary metabolites and coenzymes, fatty acid elongation, and the vast diversity of mycobacterial lipids each result from specific FAS activities. The microcompartmentalization of FAS activities in type I multienzymes may thus allow for both the controlled and concerted action of multiple FAS systems within the same cell

Structure and function of eukaryotic fatty acid synthases

“…It not only lacks many of the structural domains and expansion segments but also the C-terminal PPT domain, which in this case is encoded by a separate gene located immediately downstream of the fas gene and obviously can act in trans (Fig. 8) (Chopra et al 2002;Dym et al 2009 ;Schweizer & Hofmann, 2004). (a) The b-chain is formed by consecutive globular domains, whereas the a-chain adopts a highly intertwined structure with numerous insertions into the KS domain and a complex extension of the KR, which together form the rigid scaffold of the central wheel.…”

“…The key differences to the fungal system are : (i) the use of a single acyl transferase for loading both the substrates, (ii) the existence of a separate TE for product release as free fatty acids and (iii) the fold and mechanism of the ER domain, which is not FMN-dependent in animal FAS and has, based on sequence analysis, a classical Rossmann-fold nucleotide-binding domain (Schweizer & Hofmann, 2004 ;Smith et al 2003). Further, animal FAS does not encompass a PPT domain for cofactor attachment.…”

Inhibition of the fungal fatty acid synthase type I multienzyme complex

“…Eukaryotes and advanced prokaryotes generally use the type I fatty acid synthase system (FAS I), composed of complexes of large multifunctional enzymes. Bacteria, in contrast, use the dissociated FAS II system that consists of a set of separate enzymes, each catalyzing one of the reactions of the fatty acid synthase cycle (1). A third system exists in some parasites that use membrane-bound fatty acid elongases for the synthesis of aliphatic chains (2).…”

Design, development, synthesis, and docking analysis of 2′‐substituted triclosan analogs as inhibitors for Plasmodium falciparum Enoyl‐ACP reductase

“…Bacteria, plants, some protozoan parasites and certain mycobacteria synthesize fatty acids using type II fatty acid synthase (FAS-II) instead of the type-I fatty acid synthase (FAS-I) which is present in most eukaryotes, including the human host (1)(2)(3)(4). In type II FAS each reaction of fatty acid synthesis is catalyzed by a physically distinct enzyme in contrast to a single multifunctional enzyme in type I FAS that catalyzes all the required reactions (5).…”