Crystal Structures of the Quinone Oxidoreductase from
            <i>Thermus thermophilus</i>
            HB8 and Its Complex with NADPH: Implication for NADPH and Substrate Recognition

Shimomura, Yoshimitsu; Kakuta, Yoshimitsu; Fukuyama, Keiichi

doi:10.1128/jb.185.14.4211-4218.2003

Cited by 23 publications

(34 citation statements)

References 37 publications

(45 reference statements)

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“…The inter-subunit interactions of these domains closely resemble the oligomerization modes of their monofunctional homologues (Olsen et al 2001 ;Shimomura et al 2003). Their respective contact sites directly involve the core catalytic parts, not just additional insertions, and are crucial for the integrity and catalytic activity of both domains.…”

Section: Overall Architecture and Linkersmentioning

confidence: 89%

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

123

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: Overall Architecture and Linkersmentioning

confidence: 89%

Structure and function of eukaryotic fatty acid synthases

Maier

Leibundgut

Boehringer

et al. 2010

Quart. Rev. Biophys.

123

127

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“…2A). In dimeric MDR proteins such as the porcine fatty acid synthase (FAS) ER (17) and quinone oxidoreductase (18), the dimer interface includes the backbone hydrogen bonding across βF from each monomer to form a characteristic 12-stranded β-sheet, as well as intermonomer interactions between αF, βE, and βF (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis

Ames

Nguyen

Bruegger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a trans-acting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-Å structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.

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“…This local conformational change may induce the entire domain movement. Such domain movement is also observed in Thermus thermophilus quinone oxide reductase (QOR) (41) and Candida tropicali enoyl thioester reductase (42), although in these cases domain movement operates to close the NADP ϩ binding site upon NADP ϩ binding. A similar domain movement has also been reported for a zinc-dependent alcohol dehydrogenase (43).…”

Section: -Hd/pgr Nadpmentioning

confidence: 95%

Structural Basis of Leukotriene B4 12-Hydroxydehydrogenase/15-Oxo-prostaglandin 13-Reductase Catalytic Mechanism and a Possible Src Homology 3 Domain Binding Loop

Hori

Yokomizo

Ago

et al. 2004

Journal of Biological Chemistry

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The bifunctional leukotriene B 4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase (LTB 4 12-HD/ PGR) is an essential enzyme for eicosanoid inactivation. It is involved in the metabolism of the E and F series of 15-oxo-prostaglandins (15-oxo-PGs), leukotriene B 4 (LTB 4 ), and 15-oxo-lipoxin A 4 (15-oxo-LXA 4 ). Some nonsteroidal anti-inflammatory drugs (NSAIDs), which primarily act as cyclooxygenase inhibitors also inhibit LTB 4 12-HD/PGR activity. Here we report the crystal structure of the LTB 4 12-HD/PGR, the binary complex structure with NADP ؉ , and the ternary complex structure with NADP ؉ and 15-oxo-PGE 2 . In the ternary complex, both in the crystalline form and in solution, the enolate anion intermediate accumulates as a brown chromophore. PGE 2 contains two chains, but only the -chain of 15-oxo-PGE 2 was defined in the electron density map in the ternary complex structure. The -chain was identified at the hydrophobic pore on the dimer interface. The structure showed that the 15-oxo group forms hydrogen bonds with the 2-hydroxyl group of nicotine amide ribose of NADP ؉ and a bound water molecule to stabilize the enolate intermediate during the reductase reaction. The electron-deficient C13 atom of the conjugated enolate may be directly attacked by a hydride from the NADPH nicotine amide in a stereospecific manner. The moderate recognition of 15-oxo-PGE 2 is consistent with a broad substrate specificity of LTB 4 12-HD/PGR. The structure also implies that a Src homology domain 3 may interact with the left-handed prolinerich helix at the dimer interface and regulate LTB 4 12-HD/PGR activity by disruption of the substrate binding pore to accommodate the -chain.Eicosanoids, such as prostaglandins, leukotrienes, and lipoxins, are endogenous lipid mediators and play key roles in a wide range of normal physiological and pathophysiological processes such as host defense responses and inflammation. The dominant eicosanoids, leukotriene B 4 (LTB 4 ), 1 prostaglandin E and F (PGE and PGF), and lipoxin A 4 (LXA 4 ) are rapidly inactivated by enzymatic degradation. A bifunctional LTB 4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase (LTB 4 12-HD/PGR), a member of the zinc-independent medium chain dehydrogenase/reductase (MDR) family (1), is a key enzyme in the irreversible degradation of all three eicosanoids to remove these highly biologically active agents (2-4) (Fig. 1).PGE 2 mediates a wide range of physiological processes in a variety of tissues (Fig. 1). It is involved in the relaxation of smooth muscle cells to protect against lung inflammation (5), regulating gastric acid and mucus secretion in the stomach (6), regulating water and mineral balance in the kidney (7), as well as having roles in immune responses, thermo-regulation, and vasopermeability. Overproduction of PGE 2 induces inflammation and can have oncogenic effects (8). PGE 2 production can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs), which act as cyclooxygenase inhibitors. NSAIDs are important drugs in the treat...

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Crystal Structures of the Quinone Oxidoreductase from Thermus thermophilus HB8 and Its Complex with NADPH: Implication for NADPH and Substrate Recognition

Cited by 23 publications

References 37 publications

Structure and function of eukaryotic fatty acid synthases

Structure and function of eukaryotic fatty acid synthases

Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis

Structural Basis of Leukotriene B4 12-Hydroxydehydrogenase/15-Oxo-prostaglandin 13-Reductase Catalytic Mechanism and a Possible Src Homology 3 Domain Binding Loop

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