Linked Life Data

16220112

Source:http://linkedlifedata.com/resource/pubmed/id/16220112

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2005-10-12
pubmed:databankReference
http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819777, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819778, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819779, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819780, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819781, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819782, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819783, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY819784, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827076, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827077, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827078, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827079, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827080, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827081, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827082, http://linkedlifedata.com/resource/pubmed/xref/GENBANK/AY827084
pubmed:abstractText
Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. Genetic polymorphisms for TPMT are a major factor responsible for large individual variations in thiopurine toxicity and therapeutic effect. The present study investigated the functional effects of human TPMT variant alleles that alter the encoded amino acid sequence of the enzyme, TPMT*2, *3A, *3B, *3C and *5 to *13. After expression in COS-1 cells and correction for transfection efficiency, allozymes encoded by these alleles displayed levels of activity that varied from virtually undetectable (*3A,*3B and *5) to 98% (*7) of that observed for the wild-type allele. Although some allozymes had significant elevations in apparent Km values for 6-mercaptopurine and S-adenosyl-L-methionine (i.e. the two cosubstrates for the reaction), the level of enzyme protein was the major factor responsible for variation in activity. Quantitative Western blot analysis demonstrated that the level of enzyme protein correlated closely with level of activity for all allozymes except TPMT*5. Furthermore, protein levels correlated with rates of TPMT degradation. TPMT amino acid sequences were then determined for 16 non-human mammalian species and those sequences (plus seven reported previously, including two nonmammalian vertebrate species) were used to determine amino acid sequence conservation. Most human TPMT variant allozymes had alterations of residues that were highly conserved during vertebrate evolution. Finally, a human TPMT homology structural model was created on the basis of a Pseudomonas structure (the only TPMT structure solved to this time), and the model was used to infer the functional consequences of variant allozyme amino acid sequence alterations. These studies indicate that a common mechanism responsible for alterations in the activity of variant TPMT allozymes involves alteration in the level of enzyme protein due, at least in part, to accelerated degradation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1744-6872
pubmed:author
pubmed:issnType
Print
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
801-15
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics.
pubmed:affiliation
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine-Mayo Clinic, Rochester, Minnesota 55905, USA.
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural