Methylenetetrahydrofolate reductase

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 17: Line 17:
== Structure ==
== Structure ==
<StructureSection load='' size='400' side='right' scene='90/907473/Mthfr_protein/2'>
<StructureSection load='' size='400' side='right' scene='90/907473/Mthfr_protein/2'>
-
MTHFR occurs as a dimer(<scene name='90/907473/Mthfr_protein/2'>reload initial scene</scene>). The N- and C-terminal domains of MTHFR are joined together by a linker (red). The N-terminal domain (silver) functions as the catalytic domain to convert 5,10-MTHF to 5-MTHF (this product will be used with [[Methionine synthase]]). This domain contains FAD as a cofactor and binds to NADPH as an electron donor<ref>PMID:16114881</ref>. The C-terminal (yellow) functions as the regulatory domain and binds to SAH, to recognize the need for inhibition or activation.
+
MTHFR occurs as a <scene name='90/907473/Mthfr_protein/3'>dimer</scene>. The <scene name='90/907473/Mthfr_protein/4'>N- and C-terminal domains of MTHFR</scene> are joined together by a linker (red). The N-terminal domain (silver) functions as the catalytic domain to convert 5,10-MTHF to 5-MTHF (this product will be used with [[Methionine synthase]]). This domain contains FAD as a cofactor and binds to NADPH as an electron donor<ref>PMID:16114881</ref>. The C-terminal (yellow) functions as the regulatory domain and binds to SAH, to recognize the need for inhibition or activation.
MTHFR catalyzes the reaction using a <scene name='90/907473/Superposition/6'>ping pong mechanism</scene>, where a substrate binds and forms an intermediate before releasing the product, followed by the binding of a second substrate and later release of a second product <ref>DOI:10.1021/bi9007325</ref>.
MTHFR catalyzes the reaction using a <scene name='90/907473/Superposition/6'>ping pong mechanism</scene>, where a substrate binds and forms an intermediate before releasing the product, followed by the binding of a second substrate and later release of a second product <ref>DOI:10.1021/bi9007325</ref>.

Revision as of 22:26, 25 April 2022

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that is a regulatory agent of folate one-carbon metabolism. The enzyme is present in both eukaryotes and prokaryotes however, the structure is unique in eukaryotes as it has a SAM binding domain. The enzyme has an essential role in S-Adenosyl Methionine (SAM) regulation in order to promote homeostasis within the folate cycle. This shows the importance of MTHFR within the human body, and identifies the issues that may arise if MTHFR dysfunction occurs.

Contents

Function

Methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate to be recycled back into the folate cycle, and for aiding folate uptake in the body. This reduction reaction requires the cofactor molecule flavin adenine dinucleotide (FAD) and the second substrate nicotinamide adenine dinucleotide phosphate (NADPH) as the electron donor in the reaction. MTHFR has a unique folding structure. Its N-terminal is abundant in serine and acts as a phosphorylation site, its situated in close proximity to it's C-terminal S-adenosyl methionine (SAM) binding site. A linker joins the catalytic domain (N-terminal) to the regulatory domain (C-terminal) for interaction and increases the sensitivity to SAM binding and feedback properties.[1]

Mechanism

This reaction mechanism is characterized by a hydride transfer (highlighted in yellow) from the FADH to the partially positive 5,10-methyl group. This causes the 5-membered ring to open and Nitrogen 10 to receive the electrons that were involved in the C-N10 bond. This allows Nitrogen 10 to act as a Bronsted-Lowry base and accept the proton highlighted in green.

5,10-methylenetetrahydrofolate + NADPH + H+ → 5-methyltetrahydrofolate + NADP+


Disease

In addition to the folate cycle, MTHFR is also a major component of the homeostasis of homocysteine in the blood stream. When this homeostasis is disrupted, mutations are created that result in hyperhomocysteinemia with homocystinuria, or mild hyperhomocysteinemia. Hyperhomocysteinemia is an excess of the amino acid circulating in the body, and is a direct correlation of cardiovascular disease, Alzheimer's disease, depression, and neural tube defects within the fetus. Furthermore, homocystinuria is clinically described as the body's inability to adequately process homocysteine and the amino acid methionine. This dysfunction can be clinically presented with skeletal, vision, and blood clotting abnormalities coupled with learning disorders.

Structure

Drag the structure with the mouse to rotate

References

  1. ↑ Froese DS, Kopec J, Rembeza E, Bezerra GA, Oberholzer AE, Suormala T, Lutz S, Chalk R, Borkowska O, Baumgartner MR, Yue WW. Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition. Nat Commun. 2018 Jun 11;9(1):2261. doi: 10.1038/s41467-018-04735-2. PMID:29891918 doi:http://dx.doi.org/10.1038/s41467-018-04735-2
  2. ↑ Pejchal R, Sargeant R, Ludwig ML. Structures of NADH and CH3-H4folate complexes of Escherichia coli methylenetetrahydrofolate reductase reveal a spartan strategy for a ping-pong reaction. Biochemistry. 2005 Aug 30;44(34):11447-57. PMID:16114881 doi:10.1021/bi050533q
  3. ↑ Lee MN, Takawira D, Nikolova AP, Ballou DP, Furtado VC, Phung NL, Still BR, Thorstad MK, Tanner JJ, Trimmer EE. Functional role for the conformationally mobile phenylalanine 223 in the reaction of methylenetetrahydrofolate reductase from Escherichia coli. Biochemistry. 2009 Aug 18;48(32):7673-85. PMID:19610625 doi:10.1021/bi9007325
Retrieved from "http://52.214.119.220/wiki/index.php/Methylenetetrahydrofolate_reductase"
Personal tools