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 alpha and beta 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.

FIG. 1.

Domain organization of known type I FASs and related multienzymes. Arrows indicate open reading frames. Their subdivision into functional domains is not shown to scale. With the exception of FAS1 and FAS2, the indicated gene pairs are chromosomally linked in tandem orientation. The indicated PKS combinations encode putative heteromeric multienzymes comprising a complete set of FAS domains. Brackets indicate intramolecular FAS modules. L, acyl-CoA ligase. Adapted from references and .

FIG. 2.

Specificity of acyl binding sites and interdomain transacylation reactions in yeast FAS. Subunits α (green) and β (red) are marked by different colors. Functional domains are arranged according to the reaction sequence. The zigzag line indicates the “swinging arm” of ACP-bound phosphopantetheine. Abbreviations are defined in the text.

FIG. 3.

Norsorolinic acid. The chemical structure and hexanoic acid side chain (boxed) are shown.

FIG. 4.

Regulatory interactions of yeast transcription factors involved in ICRE-dependent FAS expression. Interactions with activating (green) or repressing (red) effects on FAS transcription are marked by different colors. TAD, transcription activation domain; RID, repressor interaction domain; SID, Sin3-interaction domain; RNA Pol II, RNA polymerase II. Adapted from reference .

FIG. 5.

Autoregulation of FAS expression (127, 177). General (Rap1, Rep1, Abf1) and ICRE transcriptional activation sites in the FAS1 and FAS2 upstream regions are indicated. The DRS in the FAS2 coding sequence is presumed to interact with Fas1 either directly or in combination with an unknown factor (X).

FIG. 6.

Proposed pathway of mycolic acid biosynthesis (186). Carbon atoms in the meromycolic and fatty acyl chains originating from either type I (red) or type II (black) FAS are marked.