Sandbox GGC2

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. Additionally, the enzyme plays rolesin cell homeostasis. It regulates the production of methionine, which is an essential amino acid that begins translation of all eukayrotic amino acids. It is also responsible for the recycling of homocysteine, which is cytotoxic to vascular endothelial cells and is an independent risk factor in coronary arterial disease.

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. hMS is important for maintaining adequate levels of methionine and AdoMet, preventing the accumulation of the cytotoxic homocysteine, and is essential in methionine metabolism. If there are elevated levels of homocysteine in the blood, there can be an increased likelihood of developing cardiovascular disease, birth defects, Down’s syndrome and affecting the development of some types of cancer. Functional deficiency of MS or MSR results in diseases such as homocystinuria, hyperhomocysteinemia and hypomethioninemia. For example, defects in the enzyme is known to causes methylcobalamin deficiency type G (cblG) [MIM:250940]; also known as homocystinuria-megaloblastic anemia complementation type G. It's an autosomal recessive inherited disease. 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. ^[2] These medical conditions may arise from either a vitamin deficiency or inborn errors in the gene encoding hMS or the gene encoding the enzyme involved in the reactivation of hMS.

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. It is a 1.6 A˚ crystal structure of the C-terminal activation domain of hMS. 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 (a small, oxygen-independent fluorescent protein that binds flavin mononucleotide) 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. The mutations are located in flexible surface loops, and thus these mutations are not thought to have a major impact on the overall structure, but rather have only localized effects.^[3]