Structure-based activity prediction for an enzyme of unknown function

Johannes C. Hermann, Ricardo Marti-Arbona, Alexander A. Fedorov, Elena Fedorov, Steven C. Almo, Brian K. Shoichet, Frank M. Raushel

Research output: Contribution to journalArticle

199 Citations (Scopus)

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 (105 M-1s-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.

Original languageEnglish (US)
Pages (from-to)775-779
Number of pages5
JournalNature
Volume448
Issue number7155
DOIs
StatePublished - Aug 16 2007

Fingerprint

S-Adenosylhomocysteine
Thermotoga maritima
Deamination
Enzymes
Proteins
Adenine
Computational Biology
X-Rays
Genome

ASJC Scopus subject areas

  • General

Cite this

Hermann, J. C., Marti-Arbona, R., Fedorov, A. A., Fedorov, E., Almo, S. C., Shoichet, B. K., & Raushel, F. M. (2007). Structure-based activity prediction for an enzyme of unknown function. Nature, 448(7155), 775-779. https://doi.org/10.1038/nature05981

Structure-based activity prediction for an enzyme of unknown function. / Hermann, Johannes C.; Marti-Arbona, Ricardo; Fedorov, Alexander A.; Fedorov, Elena; Almo, Steven C.; Shoichet, Brian K.; Raushel, Frank M.

In: Nature, Vol. 448, No. 7155, 16.08.2007, p. 775-779.

Research output: Contribution to journalArticle

Hermann, JC, Marti-Arbona, R, Fedorov, AA, Fedorov, E, Almo, SC, Shoichet, BK & Raushel, FM 2007, 'Structure-based activity prediction for an enzyme of unknown function', Nature, vol. 448, no. 7155, pp. 775-779. https://doi.org/10.1038/nature05981
Hermann JC, Marti-Arbona R, Fedorov AA, Fedorov E, Almo SC, Shoichet BK et al. Structure-based activity prediction for an enzyme of unknown function. Nature. 2007 Aug 16;448(7155):775-779. https://doi.org/10.1038/nature05981
Hermann, Johannes C. ; Marti-Arbona, Ricardo ; Fedorov, Alexander A. ; Fedorov, Elena ; Almo, Steven C. ; Shoichet, Brian K. ; Raushel, Frank M. / Structure-based activity prediction for an enzyme of unknown function. In: Nature. 2007 ; Vol. 448, No. 7155. pp. 775-779.
@article{cde301ca49e14c14b587b320d9295c18,
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 (105 M-1s-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.",
author = "Hermann, {Johannes C.} and Ricardo Marti-Arbona and Fedorov, {Alexander A.} and Elena Fedorov and Almo, {Steven C.} and Shoichet, {Brian K.} and Raushel, {Frank M.}",
year = "2007",
month = "8",
day = "16",
doi = "10.1038/nature05981",
language = "English (US)",
volume = "448",
pages = "775--779",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7155",

}

TY - JOUR

T1 - Structure-based activity prediction for an enzyme of unknown function

AU - Hermann, Johannes C.

AU - Marti-Arbona, Ricardo

AU - Fedorov, Alexander A.

AU - Fedorov, Elena

AU - Almo, Steven C.

AU - Shoichet, Brian K.

AU - Raushel, Frank M.

PY - 2007/8/16

Y1 - 2007/8/16

N2 - 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 (105 M-1s-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.

AB - 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 (105 M-1s-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.

UR - http://www.scopus.com/inward/record.url?scp=34547939672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547939672&partnerID=8YFLogxK

U2 - 10.1038/nature05981

DO - 10.1038/nature05981

M3 - Article

VL - 448

SP - 775

EP - 779

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7155

ER -