MDH Full Form

Enzymes are biological substances that catalyse chemical reactions within cells. Malate dehydrogenase is one enzyme known for its role in the Krebs cycle or tricarboxylic acid cycle. The Krebs cycle occurs in the mitochondrial matrix and is crucial to cells for their respiration. Scientists and researchers extensively study malate dehydrogenase as it has a number of isoenzymes. Within the cell, the enzyme exists in the mitochondria and cytoplasm. The enzyme speeds up the reaction to convert oxaloacetate to malate in the cytoplasm. In the mitochondria, malate dehydrogenase catalyses the conversion of malate to oxaloacetate. Now, let’s take a look at the enzyme malate dehydrogenase in detail. 

Malate dehydrogenase was discovered in 1910 by Thunberg and Stern. This ubiquitous enzyme occurs in plants, animals and microorganisms. Malate dehydrogenase is mainly found in the liver, followed by the heart, skeletal muscles, and brain. This enzyme is 90% found in the cytoplasm and 10% in the mitochondria within a cell. The enzyme is either a dimer or a tetramer depending on its location and the organism it is found in. 

Properties of Malate dehydrogenase

Some of the important properties of the enzyme malate dehydrogenase are:

• Optimum pH: 7.4
• Molecular weight: 70 kDa (kiloDalton). According to studies by Devenyi, the molecule of this enzyme is made of similar subunits. These subunits are of molecular weight between 30 to 35 kDa
• Composition: The molecule of malate dehydrogenase is made of two polypeptide chains. According to research made by Wolfe and Eberhardt in 1975, there are two sites to bind coenzymes per 70 kDa. Between 1972 and 1975, various researches and studies were conducted to report the active centres on the enzyme. In 1972, a possible Flavin mononucleotide (FMN) binding site for the enzyme was reported by Codd
• Inhibitors: Studies made by Gutman and Hartstein in 1974 and Schindler in 1975 suggest that 2-Thenoyl-trifluoroacetone and chlorothricin inhibit malate dehydrogenase activities. Moreover, iodine, cyanide, thyroxine, chlorothricin, molecular iodine and other iodinated compounds can interfere with or inactivate the enzyme. These substances basically oxidise the -SH groups of malate dehydrogenase (studies by Varrone in 1970) 
• Activators: Kiramitsu in 1968 and Silverstein and Sulebele in 1970 reported in their studies that Mercuribenzoate can activate malate dehydrogenase enzyme in low concentrations. This enzyme’s other known stimulators are zinc ions, phosphate, and arsenate
• Stability and shelf life: Malate dehydrogenase is stable for a year when stored as a suspension in ammonium sulphate at a temperature of 2 to 8 degrees centigrade

Mechanism of Malate dehydrogenase

The active site of the enzyme malate dehydrogenase has substrate and coenzyme binding sites within the protein complex. This active site is hydrophobic in nature. When the enzyme is active, it experiences a conformational change. It encloses the substrate in the active site, thereby reducing its exposure to the solvent. The enzyme also places three key residues close to the substrate. These residues form the catalytic triad and are Aspartate (Asp- 168), Histidine (His- 195), and Arginine (Arg-102). The histidine and aspartate residues act as a proton transfer system, while arginine secures the substrate. 

Malate dehydrogenase speeds up the oxidation of the hydroxyl group of malate. In the process, it uses the electron acceptor NAD+

During this process, the substrate loses a hydride ion and a proton. The NAD+takes this hydride ion to get reduced to NADH. Simultaneously, the histidine residue accepts the proton lost by the substrate, thereby getting positively charged. The negatively charged Asp-168 residue, which is positioned adjacent to the His-195, stabilises the histidine residue. This electrostatic stabilisation of the residues facilitates the proton transfer. The positively charged arginine residues help bind the carboxylates (negatively charged) to the substrate, thereby playing a role in electrostatic catalysis. 

Several researchers have identified a segment or loop in the malate dehydrogenase enzyme that takes part in the catalysis processes. This particular loop changes its conformation to protect the substrate and catalytic amino acids from the solvent. It happens only when the substrate binds to the enzyme-coenzyme complex. Moreover, this change of the loop conformation also enhances the interaction of the substrate with catalytically essential amino acids. Additionally, this segment or the loop of malate dehydrogenase is believed to be a mobile loop. So, it may be related to the determination of the rate of enzyme catalysis. 

Conclusion

Malate dehydrogenase is an enzyme responsible for cellular respiration. It is an important driving factor of the Krebs cycle. The enzyme is found in abundance in the liver, heart, skeletal muscles and brain. It also takes part in other metabolic processes in the cells, like gluconeogenesis, amino acid synthesis, etc.; in medical science, the enzyme acts as a biomarker for liver and heart injury. The enzyme is extensively researched and studied due to the existence of its various isoforms.