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Methionine adenosyltransferases in disease and regulation of gene expression

  • Full or part time

    Prof S Hasnain
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Transmethylation, the transfer of a methyl group from one molecule to another, is a fundamental chemical reaction that plays a central role in important biological processes such as gene expression, cell growth and apoptosis. The highly conserved methionine adenosyltransferase (MAT) enzymes synthesize the main source of methyl groups in all living organisms in the form of S-adenosylmethionine (SAMe). In human, there are 3 types of MAT enzymes: the catalytic subunits MATα1, found exclusively in liver and MATα2, found in extrahepatic tissues, and the regulatory subunit MATβ, which colocalises with MATα2 and can form a stable complex.

Several diseases are known to arise from dysregulation of MATs. For example, mutations involving MATα1 have links with hepatic MAT deficiency which leads to patients having hypermethioninaemia. The impact of the Arg264 mutation was hypothesized to arise from an inability of the mutant to form the dimer. We have shown that it does not prevent enzyme dimerisation but causes severe reduction of enzymatic activity, which can be restored upon complex formation either with regulatory subunit, MATβ, or a number of quinone-based compounds offering a potential therapeutic route. MAT2 is also present in nuclei where its role is poorly understood.I It has been suggested to interact with transcriptional factors MAFK and BACH1 and histone methyltransferase METTL16 (RNA N6-adenosine-methyltransferase) and facilitate target gene repression by promoting histone methylation.

The student will work on this multidisciplinary programme using molecular biology, protein chemistry, protein crystallography and human cell line experiments. Required ’wet-lab’ facilities for the project (e.g. cloning, expression and purification of proteins and cell culture) are available at our institution. Additionally, UoL has a combined SAXS/MX facility on a super bright in-house X-ray generator FR-E+ and a crystallization robot.

Candidates must have, or expect to gain, a first or strong upper second class degree (or equivalent) in a relevant discipline.

Applications will be reviewed until a suitable candidate is appointed.

Funding Notes

Open to both UK/International students with their own funding/scholarship. Applicants are encouraged to contact the Principal Supervisor directly to discuss their application/project.

Assistance will be given to those who are applying to international funding schemes. The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £3000 per year.

A tuition fee bursary may be available for well qualified and motivated applicants with First class degree.

Details of costs can be found on the University website: View Website

References

Panmanee J. et al, (2019) Control and regulation of S-Adenosylmethionine biosynthesis by the regulatory b subunit and quinolone-based compounds FEBS Journal 286(1),2135-2154

Doxtader, K.A. et al (2018) Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor Mol Cell. 71(6), 1001–1011

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