Function
Human methionine synthase,5-methyltetrahydrofolate homocysteine methyltransferase (hMS), is responsible for the synthesis of methionine from the process of transfering a methyl group methyl-cobalamin to homocysteine. [1] The resulting product along with the synthesized methionine is a enzyme-bound cob(I)alamin.
Relevance
The enzyme hMS plays a crucial role in folate metabolism because it's responsible for recycling homocysteine to make methionine. In humans, it is the only enzyme that can cleave off tetrahydrofolate (H4folate) from methyltetrahydrofolate (CH3-H4folate). Tetrahydrofolate is a very important metabolite for the biosynthesis of protein and nucleic acids. However, if there are defects, this causes methylcobalamin deficiency type G (cblG) [MIM:250940]; also known as homocystinuria-megaloblastic anemia complementation type G. It's an autosomal recessive inherited disease that in known to be related to diseases such as mental retardation, macrocytic anemia, and homocystinuria. Other defects in the enzyme could lead to mild deficiency in MS activity. Mild deficiency can cause mild hyperhomocysteinemia, a risk factor for cardiovascular disease and neural tube defects, such as folate-sensitive neural tube defects and spina bifida. Other MS mutations could also be involved in tumorigenesis and cancer. [2]
Structural highlights
Human methonine synthase exist in a which can be seen in color by polypeptide chain, which is different compared to other organism such as E. coli. Ultimately, the structural surface of the enzyme is C-shape which includes 2 polypeptide chains in a specific twisted anti-parallel beta sheet with a beta meander region. A cartoon representation of the protein shows of the protein where the exterior consists of mainly alpha helices, and the interior consist of mainly beta sheets. This activation domain interacts with the FMN-binding domain of human methionine synthase reductase (hMSR), and the interaction has higher affinity in the presence of the substrate, S-adenosyl-methionine. In the mutant strain, the , D963E and K1071N, weakens the binding between the active domain of the human methionine synthase and human methionine synthase reductase. The active site with the residues are key for the partner binding because it plays a major role n forming reactivation complexes and dimer formation.
