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Title: Structure-Based Activity Prediction for an Enzyme of Unknown Function

Abstract

With many genomes sequenced, a pressing challenge in biology is predicting the function of the proteins that the genes encode. When proteins are unrelated to others of known activity, bioinformatics inference for function becomes problematic. It would thus be useful to interrogate protein structures for function directly. Here, we predict the function of an enzyme of unknown activity, Tm0936 from Thermotoga maritima, by docking high-energy intermediate forms of thousands of candidate metabolites. The docking hit list was dominated by adenine analogues, which appeared to undergo C6-deamination. Four of these, including 5-methylthioadenosine and S-adenosylhomocysteine (SAH), were tested as substrates, and three had substantial catalytic rate constants (10{sup 5} M{sup -1} s{sup -1}). The X-ray crystal structure of the complex between Tm0936 and the product resulting from the deamination of SAH, S-inosylhomocysteine, was determined, and it corresponded closely to the predicted structure. The deaminated products can be further metabolized by T. maritima in a previously uncharacterized SAH degradation pathway. Structure-based docking with high-energy forms of potential substrates may be a useful tool to annotate enzymes for function.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929954
Report Number(s):
BNL-80555-2008-JA
TRN: US200822%%1118
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 448
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ADENINES; BIOLOGY; CRYSTAL STRUCTURE; DEAMINATION; ENZYMES; FUNCTIONS; GENES; METABOLITES; POTENTIALS; PROTEIN STRUCTURE; PROTEINS; SUBSTRATES; national synchrotron light source

Citation Formats

Hermann,J., Marti-Arbona, R., Fedorov, A., Fedorov, E., Almo, S., Shoichet, B., and Raushel, F. Structure-Based Activity Prediction for an Enzyme of Unknown Function. United States: N. p., 2007. Web. doi:10.1038/nature05981.
Hermann,J., Marti-Arbona, R., Fedorov, A., Fedorov, E., Almo, S., Shoichet, B., & Raushel, F. Structure-Based Activity Prediction for an Enzyme of Unknown Function. United States. doi:10.1038/nature05981.
Hermann,J., Marti-Arbona, R., Fedorov, A., Fedorov, E., Almo, S., Shoichet, B., and Raushel, F. Mon . "Structure-Based Activity Prediction for an Enzyme of Unknown Function". United States. doi:10.1038/nature05981.
@article{osti_929954,
title = {Structure-Based Activity Prediction for an Enzyme of Unknown Function},
author = {Hermann,J. and Marti-Arbona, R. and Fedorov, A. and Fedorov, E. and Almo, S. and Shoichet, B. and Raushel, F.},
abstractNote = {With many genomes sequenced, a pressing challenge in biology is predicting the function of the proteins that the genes encode. When proteins are unrelated to others of known activity, bioinformatics inference for function becomes problematic. It would thus be useful to interrogate protein structures for function directly. Here, we predict the function of an enzyme of unknown activity, Tm0936 from Thermotoga maritima, by docking high-energy intermediate forms of thousands of candidate metabolites. The docking hit list was dominated by adenine analogues, which appeared to undergo C6-deamination. Four of these, including 5-methylthioadenosine and S-adenosylhomocysteine (SAH), were tested as substrates, and three had substantial catalytic rate constants (10{sup 5} M{sup -1} s{sup -1}). The X-ray crystal structure of the complex between Tm0936 and the product resulting from the deamination of SAH, S-inosylhomocysteine, was determined, and it corresponded closely to the predicted structure. The deaminated products can be further metabolized by T. maritima in a previously uncharacterized SAH degradation pathway. Structure-based docking with high-energy forms of potential substrates may be a useful tool to annotate enzymes for function.},
doi = {10.1038/nature05981},
journal = {Nature},
number = ,
volume = 448,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}