Structure and function of eukaryotic fatty acid synthases

Abstract

Abstract. In all organisms, fatty acid synthesis is achieved in variations of a common cyclic reaction pathway by stepwise, iterative elongation of precursors with two-carbon extender units. In bacteria, all individual reaction steps are carried out by monofunctional dissociated enzymes, whereas in eukaryotes the fatty acid synthases (FASs) have evolved into large multifunctional enzymes that integrate the whole process of fatty acid synthesis. During the last few years, important advances in understanding the structural and functional organization of eukaryotic FASs have been made through a combination of biochemical, electron microscopic and X-ray crystallographic approaches. They have revealed the strikingly different architectures of the two distinct types of eukaryotic FASs, the fungal and the animal enzyme system. Fungal FAS is a 2Á6 MDa a 6 b 6 heterododecamer with a barrel shape enclosing two large chambers, each containing three sets of active sites separated by a central wheel-like structure. It represents a highly specialized micro-compartment strictly optimized for the production of saturated fatty acids. In contrast, the animal FAS is a 540 kDa X-shaped homodimer with two lateral reaction clefts characterized by a modular domain architecture and large extent of conformational flexibility that appears to contribute to catalytic efficiency.

The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract

“…Homozygous Acaca À/ À knockout (KO) mouse embryos were undeveloped and died, while heterozygotes were fertile with normal life spans and normal body weight. 24 Considering the function and housekeeping role of FAS and the KO mouse phenotypes, the ACACA mutation is unlikely to be the genetic cause of the CC phenotype in family CC00116. The report of the p.Arg1133His mutation as a somatic mutation in large intestine carcinoma must be considered as a passenger mutation in cancer progression.…”

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

“…It remains to be determined whether these starter units are derived from endogenous acyl-CoA molecules or are diverted from the acyl-ACP thioester intermediates on the fungal type I fatty acid synthase (FAS) of the host. It has to be noted, however, that the sequestered conformation of the ACP domains inside the two reaction chambers of the heterododecameric yeast FAS is expected to prevent direct interaction with the SAT domain of the nrPKS (43,44). In any case, the ability of fungal collaborating nrPKSs to engage in productive cross talk with the primary metabolism of the host is not the exclusive property of PKS13, nor is it limited to bacterial type II FASs as partners.…”

Glucose 6-phosphate and alcohol dehydrogenase activities are components of dynamic macromolecular depots structures

“…These organizations could provide several advantages with regard to function and also to stability of single components, as reported for the fatty acid synthase (FAS) I system, a large coordinated multifunctional enzyme which carries out fatty acids biosynthesis [2]. This complex is specifically required during the transition from the respiratory to the fermentative growth constituting an evolutionary-conserved membrane-phospholipids adaptive system able to contrast the potential denaturing conditions determined by the accumulation of ethanol.…”

“…Many complexes have been characterized and the 3D structure determined for a few of them: the fatty acid synthase complex is just an example [2]. Many, if not all, complexes in turn can assemble in dynamic multi-component macromolecular networks, called "depots" [3,4].…”