X-Ray Crystallographic and Kinetic Studies of Human Sorbitol Dehydrogenase

Pauly, T.A.; Ekstrom, J.L.; Beebe, David A.; Chrunyk, Boris A.; Cunningham, David; Griffor, Matthew C.; Kamath, Ajith V.; Lee, S.Edward; Madura, R.; Mcguire, D.; Subashi, Timothy A.; Wasilko, David J.; Watts, Paul; Mylari, Banavara L.; Oates, Peter J.; Adams, Paul D.; Rath, Virginia L.

doi:10.1016/s0969-2126(03)00167-9

Cited by 85 publications

(103 citation statements)

References 42 publications

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“…The 2-hydroxyl group of sorbitol is a critical functional group that acts as a hydrogen bond donor to an active site of SDH [15]. FDS, with substitution by fluorine at the 2-position of D-glucitol, completely abrogated the recognition by SDH [10,16]. Our cell uptake and efflux studies also support the observations by the 19 F-NMR spectroscopy and enzymatic assays described above.…”

Section: Discussionsupporting

confidence: 84%

The Synthesis of 18F-FDS and Its Potential Application in Molecular Imaging

Cao

et al. 2007

Mol Imaging Biol

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# These authors contributed equally to this work. AbstractPurpose-2-Deoxy-2-[ 18 F]fluoro-D-glucose (FDG) is the most commonly used positron emission tomography (PET) tracer for oncological and neurological imaging, but it has limitations on detecting tumor or inflammation in brain gray matter. In this study, we describe the development of 2-deoxy-2-[ 18 F]fluorosorbitol ( 18 F-FDS) and its possible application in lesion detection around brain area.Procedures-18 F-FDS was obtained by reduction of FDG using NaBH 4 (81±4% yield in 30 min). Cell uptake/efflux experiments in cell culture and small animal PET imaging on tumor and inflammation models were performed.Results-Despite the low accumulation in cell culture, 18 F-FDS had good tumor uptake and contrast in the subcutaneous U87MG tumor model (4.54%ID/g at 30 min post-injection). Minimal uptake in the normal mouse brain facilitated good tumor contrast in both U87MG and GL-26 orthotopic tumor models. 18 F-FDS also had increased uptake in the inflamed foci of the TPAinduced acute inflammation model.Conclusions-Because of the ease of synthesis and favorable in vivo kinetics, 18 F-FDS may have potential applications in certain cases where FDG is inadequate (e.g., brain tumor).

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Section: Discussionsupporting

confidence: 84%

The Synthesis of 18F-FDS and Its Potential Application in Molecular Imaging

Cao

et al. 2007

Mol Imaging Biol

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“…The classical mechanism of the MDR family requires that the zinc bound water in the binary complex be displaced by the substrate (2). However, in both ternary complexes of GlcDH, the zinc-bound water is retained, a situation also observed in the structures of an inactive T40A mutant of S. solfataricus glucose dehydrogenase, in complex with either glucose and xylose (24) and also in an inhibitor complex of sorbitol dehydrogenase (11). These structures therefore dispel the view that the substrate displaces the water as a universal feature of the mechanism of the MDR family.…”

Section: Implications For Active-site Dynamics In Catalysis By the MDmentioning

confidence: 81%

“…Biochemical, biophysical, and computational studies have suggested that as zinc is a strong Lewis acid, the water molecule it coordinates would be an hydroxide ion in the binary complex, as proposed for LADH (25), SDH (11,26), and S. solfataricus GlcDH (24). This hydroxide could then act as a base to transiently trap the proton released during formation of the alkoxide.…”

Section: Implications For Active-site Dynamics In Catalysis By the MDmentioning

confidence: 99%

“…These results have been interpreted as suggesting that two distinct five coordinated zinc species are present during the reaction cycle. The possibility of penta-coordinated zinc intermediates is further supported by the structure of the MDR enzyme human sorbitol dehydrogenase in complex with NADH, Zn 2ϩ , and an hydroxymethylated pyrimidine-based inhibitor that shows that the zinc is coordinated by two protein ligands, a water molecule and two atoms from the inhibitor (11).…”

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confidence: 96%

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Active site dynamics in the zinc-dependent medium chain alcohol dehydrogenase superfamily

Baker

Britton

Fisher

et al. 2009

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

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Despite being the subject of intensive investigations, many aspects of the mechanism of the zinc-dependent medium chain alcohol dehydrogenase (MDR) superfamily remain contentious. We have determined the high-resolution structures of a series of binary and ternary complexes of glucose dehydrogenase, an MDR enzyme from Haloferax mediterranei. In stark contrast to the textbook MDR mechanism in which the zinc ion is proposed to remain stationary and attached to a common set of protein ligands, analysis of these structures reveals that in each complex, there are dramatic differences in the nature of the zinc ligation. These changes arise as a direct consequence of linked movements of the zinc ion, a zinc-bound bound water molecule, and the substrate during progression through the reaction. These results provide evidence for the molecular basis of proton traffic during catalysis, a structural explanation for pentacoordinate zinc ion intermediates, a unifying view for the observed patterns of metal ligation in the MDR family, and highlight the importance of dynamic fluctuations at the metal center in changing the electrostatic potential in the active site, thereby influencing the proton traffic and hydride transfer events.MDR family ͉ structure ͉ zinc metalloenzyme ͉ reaction mechanism Z inc-dependent enzymes catalyze many important cellular processes (1); yet, despite this, the role played by the zinc ion in catalysis is not completely understood, partly because zinc is silent in a range of useful spectroscopic techniques, such as EPR and optical spectroscopy. One of the best characterized zinccontaining enzyme families is the Zn-dependent medium chain alcohol dehydrogenase superfamily (MDR), which catalyzes the oxidation of primary or secondary alcohols to the corresponding aldehydes or ketones using NAD(P) ϩ as a cofactor (2).The structures of many MDR family members have been determined with that of liver alcohol dehydrogenase (LADH) as the prototypical member (3). These studies have shown that the subunit of these enzymes is constructed from two domains, a nucleotide binding domain and a catalytic domain (4), with the essential zinc ion located deep in the cleft between them. The ligands to the zinc are provided by residues from the catalytic domain and, in the absence of substrate, the zinc is coordinated to the side chains of three well conserved residues, which in LADH are Cys-46, His-67, and Cys-174 (2). The tetrahedral coordination shell of the zinc is completed by a water molecule (2).In the classical text book mechanism for this enzyme family (5), this zinc-bound water molecule is suggested to be displaced by the incoming hydroxyl group of the alcohol on substrate binding, to leave the zinc ion coordinated to the substrate and the same three protein ligands as in the apo enzyme. The redox reaction requires the net removal of two hydrogen atoms from the substrate and is thought to proceed via proton loss from the substrate hydroxyl to bulk solvent by using a proton relay system to form an alkoxide intermedia...

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“…However, in HfxGDH, none of these coordinating residues is conserved, and accordingly, the structural zinc has not been detected in the crystal structures (270). Thus, the structural zinc identified in the other archaeal GDHs seems not to be functionally essential, as also described for other MDR family members (273,(275)(276)(277).…”

Section: Bacteria Eukaryamentioning

confidence: 84%

Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

Bräsen

Esser

Rauch

et al. 2014

Microbiol Mol Biol Rev

261

279

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SUMMARY The metabolism of Archaea , the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya . However, this metabolic complexity in Archaea is accompanied by the absence of many “classical” pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of “new,” unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea . In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya . Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented.

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X-Ray Crystallographic and Kinetic Studies of Human Sorbitol Dehydrogenase

Cited by 85 publications

References 42 publications

The Synthesis of 18F-FDS and Its Potential Application in Molecular Imaging

The Synthesis of 18F-FDS and Its Potential Application in Molecular Imaging

Active site dynamics in the zinc-dependent medium chain alcohol dehydrogenase superfamily

Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

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