scholarly journals Enzyme Architecture: The Role of a Flexible Loop in Activation of Glycerol-3-phosphate Dehydrogenase for Catalysis of Hydride Transfer

Biochemistry ◽  
2018 ◽  
Vol 57 (23) ◽  
pp. 3227-3236 ◽  
Author(s):  
Rui He ◽  
Archie C. Reyes ◽  
Tina L. Amyes ◽  
John P. Richard
Keyword(s):  
Hydride Transfer ◽  
Flexible Loop ◽  
Glycerol 3 Phosphate Dehydrogenase

scholarly journals Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-phosphate Dehydrogenase

ACS Catalysis ◽  
2020 ◽  
Vol 10 (19) ◽  
pp. 11253-11267
Author(s):  
Anil R. Mhashal ◽  
Adrian Romero-Rivera ◽  
Lisa S. Mydy ◽  
Judith R. Cristobal ◽  
Andrew M. Gulick ◽  
...  
Keyword(s):  
Active Site ◽  
Hydride Transfer ◽  
Side Chains ◽  
Flexible Loop ◽  
Glycerol 3 Phosphate Dehydrogenase

scholarly journals Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-Phosphate Dehydrogenase

2020 ◽  
Author(s):  
Anil Ranu Mhashal ◽  
Adrian Romero-Rivera ◽  
Lisa S. Mydy ◽  
Judith R. Cristobal ◽  
Andrew M. Gulick ◽  
...  
Keyword(s):  
Conformational Change ◽  
Critical Role ◽  
Valence Bond ◽  
Hydride Transfer ◽  
Structural Data ◽  
Wild Type ◽  
Human Form ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Important Enzyme

<div> <div> <div> <p>Glycerol-3-phosphate dehydrogenase is a biomedically important enzyme that plays a crucial role in lipid biosynthesis. It is activated by a ligand-gated conformational change that is necessary for the enzyme to reach a catalytically competent conformation capable of efficient transition state stabilization. While the human form (hlGPDH) has been the subject of extensive structural and biochemical studies, corresponding computational studies to support and extend the experimental observations have been lacking. We perform here detailed empirical valence bond and Hamiltonian replica exchange molecular dynamics simulations of wild-type hlGPDH and its variants, as well as providing a novel crystal structure of the binary hlGPDH·NAD R269A variant where the enzyme is present in the open conformation. We estimated the activation free energies for the hydride transfer reaction in wild-type and substituted variants of hlGPDH and investigated the effect of mutations on the catalysis from a detailed structural study. Our structural data and simulations also illustrate the critical role of the R269 side chain in facilitating the closure of hlGPDH into a catalytically competent conformation, through modulating the flexibility of a key catalytic loop (292-LNGQKL-297), thus rationalizing a tremendous 41,000-fold decrease experimentally in the turnover number, kcat, upon truncating this residue. Taken together, our data highlight the importance of this ligand-gated conformational change in catalysis, a feature that can be exploited both for protein engineering and for the design of novel allosteric inhibitors targeting this biomedically important enzyme.</p></div></div></div>

scholarly journals Modeling the Role of a Flexible Loop and Active Site Side Chains in Hydride Transfer Catalyzed by Glycerol-3-Phosphate Dehydrogenase

2020 ◽  
Author(s):  
Anil Ranu Mhashal ◽  
Adrian Romero-Rivera ◽  
Lisa S. Mydy ◽  
Judith R. Cristobal ◽  
Andrew M. Gulick ◽  
...  
Keyword(s):  
Conformational Change ◽  
Critical Role ◽  
Valence Bond ◽  
Hydride Transfer ◽  
Structural Data ◽  
Wild Type ◽  
Human Form ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Important Enzyme

<div> <div> <div> <p>Glycerol-3-phosphate dehydrogenase is a biomedically important enzyme that plays a crucial role in lipid biosynthesis. It is activated by a ligand-gated conformational change that is necessary for the enzyme to reach a catalytically competent conformation capable of efficient transition state stabilization. While the human form (hlGPDH) has been the subject of extensive structural and biochemical studies, corresponding computational studies to support and extend the experimental observations have been lacking. We perform here detailed empirical valence bond and Hamiltonian replica exchange molecular dynamics simulations of wild-type hlGPDH and its variants, as well as providing a novel crystal structure of the binary hlGPDH·NAD R269A variant where the enzyme is present in the open conformation. We estimated the activation free energies for the hydride transfer reaction in wild-type and substituted variants of hlGPDH and investigated the effect of mutations on the catalysis from a detailed structural study. Our structural data and simulations also illustrate the critical role of the R269 side chain in facilitating the closure of hlGPDH into a catalytically competent conformation, through modulating the flexibility of a key catalytic loop (292-LNGQKL-297), thus rationalizing a tremendous 41,000-fold decrease experimentally in the turnover number, kcat, upon truncating this residue. Taken together, our data highlight the importance of this ligand-gated conformational change in catalysis, a feature that can be exploited both for protein engineering and for the design of novel allosteric inhibitors targeting this biomedically important enzyme.</p></div></div></div>

scholarly journals Role of glycerol 3-phosphate dehydrogenase in glyceride metabolism. Effect of diet on enzyme activities in chicken liver

1975 ◽  
Vol 146 (1) ◽  
pp. 223-229 ◽  
Author(s):  
J W Harding ◽  
E A Pyeritz ◽  
E S Copeland ◽  
H B White
Keyword(s):  
Lactate Dehydrogenase ◽  
High Fat Diet ◽  
Acyl Carrier Protein ◽  
Fatty Acid Synthetase ◽  
Carrier Protein ◽  
High Fat ◽  
Carbohydrate Diet ◽  
Metabolic Role ◽  
Glycerol 3 Phosphate Dehydrogenase

1. The metabolic role of hepatic NAD-linked glycerol 3-phosphate dehydrogenase (EC 1.1.1.8) was investigated vis-a-vis glyceride synthesis, glyceride degradation and the maintainence of the NAD redox state. 2. Five-week-old chickens were placed on five dietary regimes: a control group, a group on an increased-carbohydrate-lowered-fat diet, a group on a high-fat-lowered-carbohydrate diet, a starved group and a starved-refed group. In each group the specific activity (mumol/min per g wet wt. of tissue) of hepatic glycerol 3-phosphate dehydrogenase was compared with the activities of the β-oxoacyl-(acyl-carrier protein) reductase component of fatty acid synthetase, glycerol kinase (EC 2.7.1.30) and lactate dehydrogenase (EC 1.1.1.27). 3. During starvation, the activities of glycerol 3-phosphate dehydrogenase, glycerol kinase and lactate dehydrogenase rose significantly. After re-feeding these activities returned to near normal. All three activities rose slightly on the high-fat diet. Lactate dehydrogenase activity rose slightly, whereas those of the other two enzymes fell slightly on the increased-carbohydrate-lowered-fat diet. 4. The activity of the β-oxoacyl-(acyl-carrier protein) reductase component of fatty acid synthetase, a lipid-synthesizing enzyme, contrasted strikingly with the other three enzyme activities. Its activity was slightly elevated on the increased-carbohydrate diet and significantly diminished on the high-fat diet and during starvation. 5. The changes in activity of the chicken liver isoenzyme of glycerol 3-phosphate dehydrogenase in response to dietary stresses suggest that the enzyme has an important metabolic role other than or in addition to glyceride biosynthesis.

scholarly journals Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer forE. coliThymidylate Synthase

ACS Catalysis ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 10241-10253 ◽  
Author(s):  
Ilya Gurevic ◽  
Zahidul Islam ◽  
Katarzyna Świderek ◽  
Kai Trepka ◽  
Ananda K. Ghosh ◽  
...  
Keyword(s):  
Hydride Transfer ◽  
Computational Studies

scholarly journals Role of Mitochondrial Glycerol-3-Phosphate Dehydrogenase in Metabolic Adaptations of Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1764
Author(s):  
Alena Pecinová ◽  
Lukáš Alán ◽  
Andrea Brázdová ◽  
Marek Vrbacký ◽  
Petr Pecina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Metabolism Regulation ◽  
Metabolic Adaptations ◽  
Cancer Types ◽  
Processed Form ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Rate Limiting

Prostate cancer is one of the most prominent cancers diagnosed in males. Contrasting with other cancer types, glucose utilization is not increased in prostate carcinoma cells as they employ different metabolic adaptations involving mitochondria as a source of energy and intermediates required for rapid cell growth. In this regard, prostate cancer cells were associated with higher activity of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), the key rate limiting component of the glycerophosphate shuttle, which connects mitochondrial and cytosolic processes and plays significant role in cellular bioenergetics. Our research focused on the role of mGPDH biogenesis and regulation in prostate cancer compared to healthy cells. We show that the 42 amino acid presequence is cleaved from N-terminus during mGPDH biogenesis. Only the processed form is part of the mGPDH dimer that is the prominent functional enzyme entity. We demonstrate that mGPDH overexpression enhances the wound healing ability in prostate cancer cells. As mGPDH is at the crossroad of glycolysis, lipogenesis and oxidative metabolism, regulation of its activity by intramitochondrial processing might represent rapid means of cellular metabolic adaptations.

Formation of .eta.3-cyclooctenyl complexes from hydride transfer reactions in hydrido(cycloocta-1,5-diene)tris(ligand)ruthenium(II) cations: the dominant role of steric effects

1984 ◽  
Vol 3 (10) ◽  
pp. 1485-1491 ◽  
Author(s):  
Terence V. Ashworth ◽  
Anthony A. Chalmers ◽  
Elsie Meintjies ◽  
Hester E. Oosthuizen ◽  
Eric Singleton
Keyword(s):  
Dominant Role ◽  
Hydride Transfer ◽  
Transfer Reactions ◽  
Steric Effects ◽  
Hydride Transfer Reactions

scholarly journals 1P-013 The role of the flexible loop in staphylococcal nuclease on its catalytic activity(The 46th Annual Meeting of the Biophysical Society of Japan)

2008 ◽  
Vol 48 (supplement) ◽  
pp. S22
Author(s):  
Shigehumi Tadokoro ◽  
Hironari Kamikubo ◽  
Shigeo Yamaguchi ◽  
Yoichi Yamazaki ◽  
Mikio Kataoka
Keyword(s):  
Catalytic Activity ◽  
Annual Meeting ◽  
Staphylococcal Nuclease ◽  
Flexible Loop ◽  
Biophysical Society
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