Structural and functional analysis of human thymidylate kinase isoforms

Abstract

Thymidylate kinase (TMPK) phosphorylates deoxythymidine monophosphate (dTMP) and plays an important role in genome stability. Deficiency in TMPK activity due to genetic alterations of DTYMK, i.e., the gene coding for TMPK, causes severe microcephaly in humans. However, no defects were observed in other tissues, suggesting the existence of a compensatory enzyme for dTTP synthesis. In search for this compensatory enzyme we analyzed 6 isoforms of TMPK mRNA deposited in the GenBank. Of these, only isoform 1 has been characterized and represents the known human TMPK. Our results reveal that isoform 2, 3, 4 and 5 lack essential structural elements for substrate binding and, thus, they are considered as nonfunctional isoforms. Isoform 6, however, has intact catalytic centers, i.e., dTMP-binding, DRX motif, ATP-binding p-loop and lid region, which are the key structural elements of an active TMPK, suggesting that isoform 6 may function as TMPK. When isoform 6 was expressed and purified, it showed only minimal activity (

Keywords

Thymidylate kinase; TMPK; Isoforms; DTYMK; human

Published in

Nucleosides, Nucleotides and Nucleic Acids
2022, volume: 41, number: 3, pages: 321-332

SLU Authors

• Frisk, Jun Mei Hu

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Pejler, Gunnar

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Eriksson, Staffan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

• Wang, Liya

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Global goals (SDG)

SDG3 Good health and well-being

UKÄ Subject classification

Biochemistry
Molecular Biology
Medical Genetics and Genomics

Publication identifier

• DOI: https://doi.org/10.1080/15257770.2021.2023748

Permanent link to this page (URI)

https://res.slu.se/id/publ/115184