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Structural and functional analysis of human thymidylate kinase isoforms

Frisk, Jun Mei Hu and Pejler, Gunnar and Eriksson, Staffan and Wang, Liya (2022). Structural and functional analysis of human thymidylate kinase isoforms. Nucleosides, Nucleotides and Nucleic Acids. 41 :3 , 321-332
[Research article]

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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 (<0.1%) as compared with isoform 1. A putative isoform 6 was detected in a cancer cell line, in addition to the dominant isoform 1. However, because of its low activity, isoform 6 is unlikely be able to compensate for the loss of TMPK activity caused by deletions and/or point mutations of the DTYMK gene. Thereby, future studies to identify and characterize the compensatory TMPK enzyme found in patients with DTYMK mutations may contribute to the understanding of dTTP synthesis and of the pathophysiological role of DTYMK mutations in neurodegenerative disorders.

Authors/Creators:Frisk, Jun Mei Hu and Pejler, Gunnar and Eriksson, Staffan and Wang, Liya
Title:Structural and functional analysis of human thymidylate kinase isoforms
Series Name/Journal:Nucleosides, Nucleotides and Nucleic Acids
Year of publishing :2022
Page range:321-332
Number of Pages:12
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Medical Genetics
(A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biochemistry and Molecular Biology
Keywords:Thymidylate kinase, TMPK, Isoforms, DTYMK, human
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Additional ID:
Type of IDID
Web of Science (WoS)000740103800001
ID Code:27528
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Anatomy, Physiology and Biochemistry
Deposited By: SLUpub Connector
Deposited On:11 Apr 2022 18:25
Metadata Last Modified:12 Apr 2022 05:01

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