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Sandbox GGC13

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Crystal Structure of Lactate Dehydrogenase A in complex with the inhibitor, oxamate.

Crystal Structure L-Lactate Dehydrogenase A interacting with inhibitor, Oxamate

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Lactate dehydrogenase is a ubiquitous protein found throughout nearly all living organisms. Primarily it is involved in the final step of glycolysis, the fermentation of pyruvate to lactate while recycling a reduced form of NADH. The regulation of LDH's activity is sought after due to the displayed relationship between activity and cancer cell proliferation. ^[1]

Function

Lactate Dehydrogenase(LDH) is a large, two domain- protein which catalyzes the conversion of pyruvate to lactate under anaerobic conditions.^[2] This conversion is coupled with the reduction of NAD+ to form the electron carrying NADH. Muscular LDH is involved in the Cori Cycle where it transports newly synthesized lactate to the liver. Liver LDH converts the lactate back to pyruvate in order to provide the precursor for gluconeogenesis.^[3]

Disease

Lactate dehydrogenase is found in its various isoenzyme forms throughout the body, including: brain, red blood cells, lungs, kidney, placenta, pancreas, muscle, and liver. It is kept at relatively low concentrations and is only utilized as a pathway under anaerobic conditions as it produces less ATP/glucose than oxidative phosphorylation. High levels of LDH are generally indicative of poor health. LDH translation is found to be overly expressed in pancreatic cancer and showed correlation with cell growth success rate. ^[4] ^[5]

Increased LDH levels are also associated with conditions such as Rhabdomyolysis which is characterized by the breakdown of skeletal muscle. This is due in part to LDH in red blood cells being released through hemolysis.

Conversely, LDH deficiency is also indicative of health problems. Decreased levels of LDH can lead to metabolic muscle disorders which have a number of symptoms and complications. The most serious of these being myoglobinuria and Rhabdomyolysis. Rhabdomyolysis

Structural highlights

Lactate dehydrogenase is a tetramer protein which can form five different isoenzymes.^[6] Subunits exist primarily in two isoforms: M and H, which differ in a single residue. The M subunit contains an alanine while the H subunit contains a glutamine.^[7] The combination of subunits defines which isoenzyme is formed and indicates where the enzyme will be present in the body. Lactate dehydrogenase A is composed of four M subunits. The subunits can adopt two conformations, open and closed, which determine the subunits activity. ^[8]

The active site contains three different binding pockets to accommodate the substrate, Nicotinamide, and adenine.

The substrate binding pocket relies on heavily on hydrogen binding and ionic interactions in order to effectively bind the substrate. Upon binding, the substrate binding pocket undergoes a conformational change where interactions between the substrate or inhibitor and a glutamine residue (Q99) essentially pull the active loop closed. ^[9]

The nicotinamide and adenine binding pockets work together to successfully bind NADH. Both binding pockets implement hydrogen bonding and hydrophobic interactions with their ligand fragment. In addition to the interactions within the binding pockets, NADH is also supported by ionic forces between arginine (R99) and the pyrophosphate groups. ^[10]

The hydroxyl groups of NADH's ribose fragments interacts with the H-bond network created by the substrate and asparagine (N137). ^[11]

References

^[12] ^[13] ^[14] ^[15] ^[16] ^[17]

↑ Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. PMID:19460998 doi:http://dx.doi.org/10.1126/science.1160809
↑ Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. PMID:19460998 doi:http://dx.doi.org/10.1126/science.1160809
↑ Cahn RD, Zwilling E, Kaplan NO, Levine L. Nature and Development of Lactic Dehydrogenases: The two major types of this enzyme form molecular hybrids which change in makeup during development. Science. 1962 Jun 15;136(3520):962-9. doi: 10.1126/science.136.3520.962. PMID:17796806 doi:http://dx.doi.org/10.1126/science.136.3520.962
↑ Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. PMID:19460998 doi:http://dx.doi.org/10.1126/science.1160809
↑ 10.1007/s13277-013-0679-1
↑ Cahn RD, Zwilling E, Kaplan NO, Levine L. Nature and Development of Lactic Dehydrogenases: The two major types of this enzyme form molecular hybrids which change in makeup during development. Science. 1962 Jun 15;136(3520):962-9. doi: 10.1126/science.136.3520.962. PMID:17796806 doi:http://dx.doi.org/10.1126/science.136.3520.962
↑ Eventoff W, Rossmann MG, Taylor SS, Torff HJ, Meyer H, Keil W, Kiltz HH. Structural adaptations of lactate dehydrogenase isozymes. Proc Natl Acad Sci U S A. 1977 Jul;74(7):2677-81. PMID:197516
↑ Poli G, Granchi C, Aissaoui M, Minutolo F, Tuccinardi T. Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. Molecules. 2017 Dec 13;22(12). pii: molecules22122217. doi:, 10.3390/molecules22122217. PMID:29236080 doi:http://dx.doi.org/10.3390/molecules22122217
↑ Poli G, Granchi C, Aissaoui M, Minutolo F, Tuccinardi T. Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. Molecules. 2017 Dec 13;22(12). pii: molecules22122217. doi:, 10.3390/molecules22122217. PMID:29236080 doi:http://dx.doi.org/10.3390/molecules22122217
↑ Poli G, Granchi C, Aissaoui M, Minutolo F, Tuccinardi T. Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. Molecules. 2017 Dec 13;22(12). pii: molecules22122217. doi:, 10.3390/molecules22122217. PMID:29236080 doi:http://dx.doi.org/10.3390/molecules22122217
↑ Poli G, Granchi C, Aissaoui M, Minutolo F, Tuccinardi T. Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. Molecules. 2017 Dec 13;22(12). pii: molecules22122217. doi:, 10.3390/molecules22122217. PMID:29236080 doi:http://dx.doi.org/10.3390/molecules22122217
↑ Poli G, Granchi C, Aissaoui M, Minutolo F, Tuccinardi T. Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. Molecules. 2017 Dec 13;22(12). pii: molecules22122217. doi:, 10.3390/molecules22122217. PMID:29236080 doi:http://dx.doi.org/10.3390/molecules22122217
↑ Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. PMID:19460998 doi:http://dx.doi.org/10.1126/science.1160809
↑ 10.1007/s13277-013-0679-1
↑ Eventoff W, Rossmann MG, Taylor SS, Torff HJ, Meyer H, Keil W, Kiltz HH. Structural adaptations of lactate dehydrogenase isozymes. Proc Natl Acad Sci U S A. 1977 Jul;74(7):2677-81. PMID:197516
↑ Cahn RD, Zwilling E, Kaplan NO, Levine L. Nature and Development of Lactic Dehydrogenases: The two major types of this enzyme form molecular hybrids which change in makeup during development. Science. 1962 Jun 15;136(3520):962-9. doi: 10.1126/science.136.3520.962. PMID:17796806 doi:http://dx.doi.org/10.1126/science.136.3520.962
↑ doi: https://dx.doi.org/10.1002/mus.880181413

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	The hydroxyl groups of NADH's ribose fragments interacts with the H-bond network created by the substrate and asparagine (N137). <ref>DOI 10.3390/molecules22122217</ref>		The hydroxyl groups of NADH's ribose fragments interacts with the H-bond network created by the substrate and asparagine (N137). <ref>DOI 10.3390/molecules22122217</ref>
-	<scene name='78/781197/~~Close up interactions between the inhibitor, oxamate and the cofactor, NADH.~~/1'>Simplified wireframe model displaying the inhibitor-NADH Hydrogen bond network involving asparagine.</scene>	+	<scene name='78/781197/Oxamate_and_nadh/1'>Simplified wireframe model displaying the inhibitor-NADH Hydrogen bond network involving asparagine.</scene>

Sandbox GGC13

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Revision as of 03:21, 22 April 2018

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