a detailed investigation of two enzymes and interaction profiling of FDA-approved nucleoside analog drugs with 23 enzymes
Egeblad, Louise
(2011).
Structural and functional studies of enzymes in nucleotide metabolism.
Diss. (sammanfattning/summary)
Uppsala :
Sveriges lantbruksuniv.,
Acta Universitatis Agriculturae Sueciae, 1652-6880
; 2011:11
ISBN 978-91-576-7546-0
[Doctoral thesis]
![]() |
PDF
5MB |
Abstract
Enzymes in nucleotide metabolism serve as the producers of the building blocks for DNA and RNA. From a medical perspective, nucleotide metabolism, and in particular salvage pathway enzymes, have attracted special interest, as nucleoside prodrugs given in the treatment of cancer and HIV are converted into their active metabolite forms by these enzymes.
In this thesis, two enzymes; uridine monophosphate kinase (UMPK) from Ureaplasma parvum (Up) and human phosphoribosyltransferase domain containing protein 1 (PRTFDC1), have been investigated. Furthermore, a nucleoside analog library (NAL) consisting of 45 FDA-approved nucleoside analogs has been developed.
The structure of Up-UMPK revealed that it was a hexamer. Kinetic constants were determined for UMP and ATP. UTP was a competitive inhibitor of UMP, and a non-competitive inhibitor of ATP. In contrast to other bacterial UMPKs, Up-UMPK was not activated by GTP.
PRTFDC1 is a homolog of hypoxanthine-guanine phosphoribosyltransferase (HPRT). Mutations in HPRT are associated with Lesch-Nyhan syndrome. The three-dimensional structures of PRTFDC1 and HRPT are very similar. Even though PRTFDC1 recognizes guanine and hypoxanthine as substrates, the functional turnover rates are less than 1% of the activity of HPRT.
NAL was screened using the high-throughput method, differential static light scattering (DSLS). An interaction profile of 23 enzymes involved in nucleotide metabolism and NAL was revealed. Interactions were detected for uridine phosphorylase 1 (UPP1) and guanine deaminase (GDA) with eight and six nucleoside prodrugs, respectively. The knowledge gained from this study can be important in the future search for drug lead candidates for UPP1 and GDA.
Authors/Creators: | Egeblad, Louise | ||||||||
---|---|---|---|---|---|---|---|---|---|
Title: | Structural and functional studies of enzymes in nucleotide metabolism | ||||||||
Subtitle: | a detailed investigation of two enzymes and interaction profiling of FDA-approved nucleoside analog drugs with 23 enzymes | ||||||||
Series Name/Journal: | Acta Universitatis Agriculturae Sueciae | ||||||||
Year of publishing : | 2011 | ||||||||
Number: | 2011:11 | ||||||||
Number of Pages: | 81 | ||||||||
Papers/manuscripts: |
| ||||||||
Place of Publication: | Uppsala | ||||||||
Publisher: | Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences | ||||||||
ISBN for printed version: | 978-91-576-7546-0 | ||||||||
ISSN: | 1652-6880 | ||||||||
Language: | English | ||||||||
Publication Type: | Doctoral thesis | ||||||||
Full Text Status: | Public | ||||||||
Agris subject categories.: | L Animal production > L50 Animal physiology and biochemistry | ||||||||
Subjects: | (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 (A) Swedish standard research categories 2011 > 1 Natural sciences > 106 Biological Sciences (Medical to be 3 and Agricultural to be 4) > Biophysics (A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 304 Medical Biotechnology > Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) | ||||||||
Agrovoc terms: | metabolism, nucleotides, ureaplasma, phosphoribosyltransferase | ||||||||
Keywords: | Nucleotide metabolism, Nucleoside analogs, Ureaplasma parvum, Uridine monophosphate kinase, Phosphoribosyltransferase domain containing protein 1, Nucleoside analog library, Differential static light scattering, Enzyme kinetics, Crystal structure | ||||||||
URN:NBN: | urn:nbn:se:slu:epsilon-e-88 | ||||||||
Permanent URL: | http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-e-88 | ||||||||
ID Code: | 8107 | ||||||||
Faculty: | VH - Faculty of Veterinary Medicine and Animal Science | ||||||||
Department: | (VH) > Dept. of Anatomy, Physiology and Biochemistry | ||||||||
Deposited By: | Louise Egeblad | ||||||||
Deposited On: | 09 May 2011 11:03 | ||||||||
Metadata Last Modified: | 17 Oct 2019 11:30 |
Repository Staff Only: item control page