Structural and functional organization of the animal fatty acid synthase

Smith, Stuart; Witkowski, Andrzej; Joshi, Anil K.

doi:10.1016/s0163-7827(02)00067-x

Cited by 563 publications

(454 citation statements)

References 104 publications

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“…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.…”

Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

119

127

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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.

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Section: Domain Composition and Reaction Cyclementioning

confidence: 99%

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

119

127

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“…FAS and ACC catalyze the synthesis of fatty acids, and are important enzymes in lipogenesis and fat accumulation (Smith et al, 2003;Tong, 2005;Maier et al, 2008). The present results show that with increasing energy level, the expression of FAS and ACC mRNA increased in adipose tissue (Figure 2A) and the liver ( Figure 2B).…”

Section: Gene Expression and Levels Of Proteins Associated With Lipidmentioning

confidence: 53%

The molecular mechanism of fat accumulation changes in Black-Bone chickens with different energy intakes

Qi¹,

Sun²,

HaiMing³

et al. 2012

J. Anim. Feed Sci.

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To investigate the molecular mechanism by which diets of different energy levels alter fat accumulation, 120 Black-Bone chickens were divided into 3 groups and fed diets with varying energy levels for six weeks (low: 3.02 Mcal/kg, moderate: 3.22 Mcal/kg, high: 3.42 Mcal/kg). The high-energy diet increased the concentration of blood lipids. Furthermore, high-energy intake inhibited the activities of several serum lipases. Histological sections showed over-synthesis of lipids in the livers of chickens fed high-energy diets. Data from western blotting and PCR analyses indicated that key factors for lipogenesis, regulatory transcription factors and fatty acid transporters, were up-regulated, while key factors for lipolysis were down-regulated. Chickens fed low-energy diets showed opposite results. In conclusion, varying energy levels of diets affect fat accumulation in Black-Bone chickens through changed expression of metabolic regulators.

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“…Similarly, diacylglycerol O-acyltransferse-2 has a role in providing a skin barrier [3]. These enzymes, as well as acetyl-coenzyme A carboxylase (ACC) 1 and 2 [4], fatty acid synthetase [5] and mitochondrial glycerol-3-phosphate acyltransferase-1 [6], are key enzymes in the de novo synthesis of triacylglycerol. Of central interest are ACC1 and 2, since they directly generate malonyl-CoA, which plays a dual role in the liver [4].…”

Section: The Premisementioning

confidence: 99%

Targeting energy expenditure via fuel switching and beyond

Geisler

2010

Diabetologia

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Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an overnutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

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Structural and functional organization of the animal fatty acid synthase

Cited by 563 publications

References 104 publications

Structure and function of eukaryotic fatty acid synthases

Structure and function of eukaryotic fatty acid synthases

The molecular mechanism of fat accumulation changes in Black-Bone chickens with different energy intakes

Targeting energy expenditure via fuel switching and beyond

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