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==Malate Dehydrogenase==
[[Malate dehydrogenase|Malate Dehydrogenase]] (MDH)(PDB entry [http://www.pdb.org/pdb/explore/explore.do?structureId=2X0I 2x0i])  is most known for its role in the metabolic pathway in the tricarboxylic acid cycle or Kreb's Cycle which is critical to cellular respiration in cells [http://en.wikipedia.org/wiki/Citric_acid_cycle]; however, the enzyme is also in many other metabolic pathways such as glyoxylate bypass, amino acid synthesis, glucogenesis, and oxidation/reduction balance <ref>PMID:12537350</ref>. It is classified as a oxidoreductase[http://en.wikipedia.org/wiki/Oxidoreductase]. Malate Dehydrogenase has been extensively studied due to its many isozymes <ref>PMID:20173310</ref>. The enzyme exists in two places inside a cell, in the mitochondria and cytoplasm. In the mitochondria, the enzyme catalyzes the reaction of malate to oxaloacetate; but in the cytoplasm, the enzyme catalyzes oxaloacetate to malate to allow transport <ref>PMID:20173310</ref>. This conversion is an essential catalytic step in each different metabolic mechanism. The enzyme malate dehydrogenase is composed of either a dimer or tetramer depending on the location and organism <ref>PMID: 9834842</ref>. During catalysis, the enzyme subunits are non-cooperative between active sites. The mitochondrial MDH is complexly, allosterically controlled by citrate, but no other known metabolic regulation mechanisms have been discovered. Further, the exact mechanism of regulation has yet to be discovered <ref>PMID:7574693</ref>. Kinetically, the pH of optimization is 7.6 for oxaloacetate conversion and 9.6 for malate conversion. The reported K(m) value for malate conversion is 215 uM and the V(max) value is 87.8 uM/min <ref>PMID:19277715</ref>.{{STRUCTURE_2x0i |  PDB=2x0i  |  SCENE=  }}
Malate Dehydrogenase (MDH)(PDB entry [http://www.pdb.org/pdb/explore/explore.do?structureId=2X0I 2x0i])  is most known for its role in the metabolic pathway in the tricarboxylic acid cycle or Kreb's Cycle which is critical to cellular respiration in cells [http://en.wikipedia.org/wiki/Citric_acid_cycle]; however, the enzyme is also in many other metabolic pathways such as glyoxylate bypass, amino acid synthesis, glucogenesis, and oxidation/reduction balance <ref>PMID:12537350</ref>. It is classified as a oxidoreductase[http://en.wikipedia.org/wiki/Oxidoreductase]. Malate Dehydrogenase has been extensively studied due to its many isozymes <ref>PMID:20173310</ref>. The enzyme exists in two places inside a cell, in the mitochondria and cytoplasm. In the mitochondria, the enzyme catalyzes the reaction of malate to oxaloacetate; but in the cytoplasm, the enzyme catalyzes oxaloacetate to malate to allow transport <ref>PMID:20173310</ref>. This conversion is an essential catalytic step in each different metabolic mechanism. The enzyme malate dehydrogenase is composed of either a dimer or tetramer depending on the location and organism <ref>PMID: 9834842</ref>. During catalysis, the enzyme subunits are non-cooperative between active sites. The mitochondrial MDH is complexly, allosterically controlled by citrate, but no other known metabolic regulation mechanisms have been discovered. Further, the exact mechanism of regulation has yet to be discovered <ref>PMID:7574693</ref>. Kinetically, the pH of optimization is 7.6 for oxaloacetate conversion and 9.6 for malate conversion. The reported K(m) value for malate conversion is 215 uM and the V(max) value is 87.8 uM/min <ref>PMID:19277715</ref>.{{STRUCTURE_2x0i |  PDB=2x0i  |  SCENE=  }}
 
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==Structure==
==Structure==
The secondary structure of a single subunit contains a <scene name='Malate_dehydrogenase/Beta_sheeting_backbone/1'>9 beta sheet parallel backbone</scene> wrapped by <scene name='Malate_dehydrogenase/Alpha_wrapping_betas/1'>9 large alpha helices</scene>. Near the sodium bound end, 4 small anti-parallel beta sheets and 1 small alpha helix enable a turn in the residue chain<scene name='Jake_Ezell_Sandbox_2/Small_turn/1'>(small turn)</scene>. Opposite the sodium bound ligand, 6 alpha helices point towards a common point, three on each side of the beta sheet backbone.  The alpha helices form a <scene name='Jake_Ezell_Sandbox_2/Small_groove_nad/1'>small groove</scene> for a NAD+ cofactor to attach near the beta sheeting. The structure most nearly resembles an alternating alpha/beta classification. As for the 3D structure, the enzyme forms a sort of  
The secondary structure of a single subunit contains a <scene name='Malate_dehydrogenase/Beta_sheeting_backbone/1'>9 beta sheet parallel backbone</scene> wrapped by <scene name='Malate_dehydrogenase/Alpha_wrapping_betas/1'>9 large alpha helices</scene>. Near the sodium bound end, 4 small anti-parallel beta sheets and 1 small alpha helix enable a turn in the residue chain<scene name='Jake_Ezell_Sandbox_2/Small_turn/1'>(small turn)</scene>. Opposite the sodium bound ligand, 6 alpha helices point towards a common point, three on each side of the beta sheet backbone.  The alpha helices form a <scene name='Jake_Ezell_Sandbox_2/Small_groove_nad/1'>small groove</scene> for a NAD+ cofactor to attach near the beta sheeting. The structure most nearly resembles an alternating alpha/beta classification. As for the 3D structure, the enzyme forms a sort of  
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==Evolutionary Divergence==
==Evolutionary Divergence==
The evolutionary past of MDH shows a divergence to form lactate dehydrogenase (LDH) which functions in a very similar way to MDH. Although there is a very low sequence conservation among MDH and LDH’s [http://blast.ncbi.nlm.nih.gov/Blast.cgi] the structure of the enzyme has remained relatively conserved. The key difference between the two is in the substrate: LDH catalyzes pyruvate to lactate.
The evolutionary past of MDH shows a divergence to form lactate dehydrogenase (LDH) which functions in a very similar way to MDH. Although there is a very low sequence conservation among MDH and LDH’s [http://blast.ncbi.nlm.nih.gov/Blast.cgi] the structure of the enzyme has remained relatively conserved. The key difference between the two is in the substrate: LDH catalyzes pyruvate to lactate.
== 3D Structures of Malate Dehydrogenase ==
The holo-MDH contains NAD or its derivatives while the apo-MDH lacks it.
=== Holo-MDH ===
[[2x0r]] – HmMDH (mutant)+NAD - Haloarcula marismortui
[[1o6z]] - HmMDH (mutant)+NADH
[[1hlp]] – HmMDH+NAD
[[1x0i]] – AfMDH+NADH – Archaeoglobus fulgidus
[[2x0j]] - AfMDH+etheno-NAD
[[1hlp]] – HmMDH+NAD
[[1x0i]] – AfMDH+NADH
[[2x0j]] - AfMDH+etheno-NAD
[[1ib6]], [[1ie3]] – EcMDH (mutant)+NAD - Escherichia coli
[[1eMDH]] – EcMDH+NAD+citrate
[[1cMDH]] - EcMDH+citrate
[[3i0p]] – MDH+NAD – Entamoeba histolytica
[[3gvh]] – BmMDH+NAD – Brucella melitensis
3gvi - BmMDH+ADP
2hjr – MDH+adenosine diphosphoribose – Cryptosporidium parvum
2dfd – MDH+NAD – human type 2
1wze – TfMDH (mutant)+NAD – Thermus flavus
1wzi - TfMDH (mutant)+NDP
1bdm - TfMDH (mutant)+beta-6-hydroxy-1,4,5,6-tetrhydronicotinamide adenine dinucleotide
1bMDH – TfMDH+NAD
1y7t – TtMDH+NADPH – Thermus thermophilus
2cvq - TtMDH+NADP
1v9n – MDH+NADPH – Pyrococcus horikoshii
1z2i – MDH+NAD – Agrobacterium tumefaciens
1uxg, 1uxh, 1uxi, 1uxj, 1uxk, 1ur5 – MDH (mutant)+NAD – Chloroflexus aurantiacus
1guz, 1guy, 1gv0 – CvMDH+NAD – Chlorobium vibrioforme
1civ – MDH+NADP – Flaveria bidentis
1b8u, 1b8v – AaMDH+NAD - Aquaspirillum arcticum
5MDHh – SsMDH+NAD+alpha-ketomalonic acid – Sus scrofa
4MDHh – SsMDH+NAD
=== apo-MDH ===
2j5r, 2j5k, 2j5q, 1d3a – HmMDH
2hlp – HmMDH (mutant)
3hhp, 2pwz – EcMDH
3fi9 – MDH – Porphyromonas gingivalis
3d5t - MDH – Burkholderia pseudomallei
2d4a – MDH – Aeropyrum pernix
1iz9 - TtMDH
1sev, 1smk – MDH – Citrullus lanatus
1gv1 – CvMDH
1b8p – AaMDH
7MDHh – MDH – Sorgum bicolor
1mld – SsMDH


==Additional Resources==
==Additional Resources==

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Jake Ezell, David Canner, Alexander Berchansky, Joshua Johnson, Michal Harel, Jaime Prilusky, Joel L. Sussman, Angel Herraez
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