Malate dehydrogenase

Function Malate Dehydrogenase (MDH)(PDB entry 2x0i) is most known for its role in the metabolic pathway of the tricarboxylic acid cycle, also know as the Kreb's Cycle, which is critical to cellular respiration in cells [1]; however, the enzyme is also in many other metabolic pathways such as glyoxylate bypass, amino acid synthesis, glucogenesis, and oxidation/reduction balance . It is classified as an oxidoreductase[2]. Malate Dehydrogenase has been extensively studied due to its many isozymes . The enzyme exists in two places inside a cell: the mitochondria and cytoplasm. In the mitochondria, the enzyme catalyzes the reaction of malate to oxaloacetate; however, in the cytoplasm, the enzyme catalyzes oxaloacetate to malate to allow transport . 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 of the enzyme and the organism it is located in . 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 . 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 . For halophilic MDH details see Halophilic malate dehydrogenase. See also: Krebs cycle carbons Krebs cycle importance Krebs cycle overview Krebs cycle step 8 Structure The secondary structure of a single subunit contains a wrapped by . Near the sodium bound end, 4 small anti-parallel beta sheets and 1 small alpha helix enable a turn in the residue chain. 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 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 for the substrate to bind. Mechanism The mechanism of catalysis is dependent on . These residues are HIS 195 and ASP 168, which are both involved in hydrogen bonding, ASP 53 associated with , and a triad of arginine residues at 102, 109, and 171. During the conversion of malate to oxaloacetate, a key conformational change occurs on the binding of substrate in which a “loop” flips into an up position to block the active site from the solvent. When this occurs, the other residues in the active site are brought closer to the substrate to enable the conversion. R102 and R109 are involved in this loop flip and thus invariant. After the loop flip, the malate complex is stabilized via hydrogen bonding before accepting a proton transfer from NADH to form oxaloacetate . 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 [3] the structure of the enzyme has remained relatively conserved. The key difference between the two is in the substrate: LDH catalyzes pyruvate to lactate.

spinqualitylabelsall models Malate dehydrogenase complex with NAD, sulfate and Na+ ion (purple) (PDB code 2x0i) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

3D Structures of Malate Dehydrogenase3D Structures of Malate Dehydrogenase

Updated on 11-February-2016

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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
    
  • 1emd – EcMDH+NAD+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-tetrahydronicotinamide adenine dinucleotide
    
  • 1bmd – 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 – ChaMDH (mutant)+NAD – Chloroflexus aurantiacus
    
  • 1guz, 1guy, 1gv0 – CvMDH+NAD – Chlorobium vibrioforme
    
  • 1civ – MDH+NADP – Flaveria bidentis
    
  • 1b8u, 1b8v – AaMDH+NAD - Aquaspirillum arcticum
    
  • 5mdh – pMDH+NAD+alpha-ketomalonic acid – pig
    
  • 4mdh – pMDH+NAD
    
  • 4i1i – LmMd + NAD – Leishmania major
    
  • 4plh, 4plt – ApMd + NAD + oxamate – Apicomplexa
    
  • 4plv, 4plw – ApMd + NAD + lactate
    
  • 4ply – ApMd + NAD + malate
    
  • 4ros – MeMd + oxaloacetate + ADPR – Methylobacterium extorquens
    
• apo-MDH
  • 2j5r, 2j5k, 2j5q, 1d3a, 4jco – HmMDH
    
  • 2hlp – HmMDH (mutant)
    
  • 3hhp, 2pwz – EcMDH
    
  • 3fi9 – MDH – Porphyromonas gingivalis
    
  • 3d5t - MDH – Burkholderia pseudomallei
    
  • 2d4a – MDH – Aeropyrum pernix
    
  • 1iz9, 4kde, 4kdf - TtMDH
    
  • 1sev, 1smk – MDH – Citrullus lanatus
    
  • 1gv1 – CvMDH
    
  • 1b8p – AaMDH
    
  • 7mdh – MDH – Sorgum bicolor
    
  • 1mld – pMDH
    
  • 2cmd - EcMd+citrate
    
  • 3nep – Md – Salinibacter ruber
    
  • 3p7m – Md – Francisella tularensis
    
  • 3tl2 – Md – Bacillus anthracis
    
  • 4e0b – Md – Vibrio vulnificus
    
  • 4h7p - LmMd
    
  • 4bgt – CaMd
    
  • 4cl3 – ChaMd
    
  • 4bgu – Md – Haloferax volcanii
    
  • 4bgv – Md – Picrophilus torridus
    
  • 4ror – MeMd
    
  • 4tvo – Md – Mycobacterium tubrtculosis
    

Additional ResourcesAdditional Resources

• Carbohydrate Metabolism
• Krebs cycle step 8