Document Detail


Functionality of alternative splice forms of the first enzymes involved in human molybdenum cofactor biosynthesis.
MedLine Citation:
PMID:  11891227     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In humans, genetic deficiencies of enzymes involved in molybdenum cofactor biosynthesis trigger an autosomal recessive and usually fatal disease with severe mostly neurological symptoms. In each of the three biosynthesis steps, at least two proteins or domains are linked for catalysis. For steps 1 and 2, bicistronic mocs (molybdenum cofactor synthesis) mRNAs were found (mocs1 and mocs2) that have been proposed to encode two separate proteins (A and B). In both cases, the A proteins share a highly conserved ubiquitin-like double glycine motif, which is functionally important at least for the small subunit of molybdopterin (MPT) synthase (MOCS2A). Besides the bicistronic form of mocs1, two alternative splice transcripts were found, resulting in the expression of multidomain proteins embodying both MOCS1A, but without the double glycine motif, and the entire MOCS1B. Here we describe the first functional characterization of the human proteins MOCS1A and MOCS1B as well as the MOCS1A-MOCS1B fusion proteins that catalyze the formation of precursor Z, a 6-alkyl pterin with a cyclic phosphate, the immediate precursor of MPT in molybdenum cofactor biosynthesis. High level expression of MOCS1A and MOCS1B in Escherichia coli resulted in the formation and accumulation of precursor Z that was subsequently converted to MPT. We showed that for catalytic activity MOCS1A needs an accessible C-terminal double glycine motif. In the MOCS1A-MOCS1B fusion proteins lacking the MOCS1A double glycines, only MOCS1B activity could be detected. No evidence was found for an expression of MOCS1B from the bicistronic mocs1A-mocs1B splice type I cDNA, indicating that MOCS1B is only expressed as a fusion to an inactive MOCS1A. Comparative mutational studies of MOCS1A and the small subunit of the E. coli MPT synthase (MoaD) indicate a different function of the double glycine motifs in both proteins.
Authors:
Petra Hänzelmann; Gunter Schwarz; Ralf R Mendel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-03-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-05-20     Completed Date:  2002-06-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18303-12     Citation Subset:  IM    
Affiliation:
Institute of Plant Biology, Technical University of Braunschweig, D-38023 Braunschweig, Germany.
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing*
Amino Acid Sequence
Base Sequence
Coenzymes*
DNA Primers
Glycine / chemistry,  metabolism
Hela Cells
Humans
Metalloproteins / biosynthesis*
Molecular Sequence Data
Mutagenesis, Site-Directed
Nuclear Proteins / chemistry,  genetics
Pteridines
Sequence Homology, Amino Acid
Sulfurtransferases / chemistry,  genetics
Chemical
Reg. No./Substance:
0/Coenzymes; 0/DNA Primers; 0/MOCS1 protein, human; 0/Metalloproteins; 0/Nuclear Proteins; 0/Pteridines; 56-40-6/Glycine; 73508-07-3/molybdenum cofactor; EC 2.8.1.-/Sulfurtransferases; EC 2.8.1.-/molybdopterin synthase

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