Prediction of enzymatic pathways by integrative pathway mapping

Sara Calhoun, Magdalena Korczynska, Daniel J. Wichelecki, Brian San Francisco, Suwen Zhao, Dmitry A. Rodionov, Matthew W. Vetting, Nawar F. Al-Obaidi, Henry Lin, Matthew J. O’Meara, David A. Scott, John H. Morris, Daniel Russel, Steven C. Almo, Andrei L. Osterman, John Alan Gerlt, Matthew P. Jacobson, Brian K. Shoichet, Andrej Sali

Research output: Contribution to journalArticle

Abstract

The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology.

Original languageEnglish (US)
Article numbere31097
JournaleLife
Volume7
DOIs
StatePublished - Jan 29 2018

Fingerprint

Metabolic Networks and Pathways
Enzymes
Crystallography
Metabolomics
Systems Biology
Haemophilus influenzae
Metabolites
Computational methods
Screening
Ligands
Substrates
Proteins
Experiments
gulonic acid

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Calhoun, S., Korczynska, M., Wichelecki, D. J., San Francisco, B., Zhao, S., Rodionov, D. A., ... Sali, A. (2018). Prediction of enzymatic pathways by integrative pathway mapping. eLife, 7, [e31097]. https://doi.org/10.7554/eLife.31097

Prediction of enzymatic pathways by integrative pathway mapping. / Calhoun, Sara; Korczynska, Magdalena; Wichelecki, Daniel J.; San Francisco, Brian; Zhao, Suwen; Rodionov, Dmitry A.; Vetting, Matthew W.; Al-Obaidi, Nawar F.; Lin, Henry; O’Meara, Matthew J.; Scott, David A.; Morris, John H.; Russel, Daniel; Almo, Steven C.; Osterman, Andrei L.; Gerlt, John Alan; Jacobson, Matthew P.; Shoichet, Brian K.; Sali, Andrej.

In: eLife, Vol. 7, e31097, 29.01.2018.

Research output: Contribution to journalArticle

Calhoun, S, Korczynska, M, Wichelecki, DJ, San Francisco, B, Zhao, S, Rodionov, DA, Vetting, MW, Al-Obaidi, NF, Lin, H, O’Meara, MJ, Scott, DA, Morris, JH, Russel, D, Almo, SC, Osterman, AL, Gerlt, JA, Jacobson, MP, Shoichet, BK & Sali, A 2018, 'Prediction of enzymatic pathways by integrative pathway mapping', eLife, vol. 7, e31097. https://doi.org/10.7554/eLife.31097
Calhoun S, Korczynska M, Wichelecki DJ, San Francisco B, Zhao S, Rodionov DA et al. Prediction of enzymatic pathways by integrative pathway mapping. eLife. 2018 Jan 29;7. e31097. https://doi.org/10.7554/eLife.31097
Calhoun, Sara ; Korczynska, Magdalena ; Wichelecki, Daniel J. ; San Francisco, Brian ; Zhao, Suwen ; Rodionov, Dmitry A. ; Vetting, Matthew W. ; Al-Obaidi, Nawar F. ; Lin, Henry ; O’Meara, Matthew J. ; Scott, David A. ; Morris, John H. ; Russel, Daniel ; Almo, Steven C. ; Osterman, Andrei L. ; Gerlt, John Alan ; Jacobson, Matthew P. ; Shoichet, Brian K. ; Sali, Andrej. / Prediction of enzymatic pathways by integrative pathway mapping. In: eLife. 2018 ; Vol. 7.
@article{2132ff67a23f4b58bc2743937a52ddb6,
title = "Prediction of enzymatic pathways by integrative pathway mapping",
abstract = "The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology.",
author = "Sara Calhoun and Magdalena Korczynska and Wichelecki, {Daniel J.} and {San Francisco}, Brian and Suwen Zhao and Rodionov, {Dmitry A.} and Vetting, {Matthew W.} and Al-Obaidi, {Nawar F.} and Henry Lin and O’Meara, {Matthew J.} and Scott, {David A.} and Morris, {John H.} and Daniel Russel and Almo, {Steven C.} and Osterman, {Andrei L.} and Gerlt, {John Alan} and Jacobson, {Matthew P.} and Shoichet, {Brian K.} and Andrej Sali",
year = "2018",
month = "1",
day = "29",
doi = "10.7554/eLife.31097",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Prediction of enzymatic pathways by integrative pathway mapping

AU - Calhoun, Sara

AU - Korczynska, Magdalena

AU - Wichelecki, Daniel J.

AU - San Francisco, Brian

AU - Zhao, Suwen

AU - Rodionov, Dmitry A.

AU - Vetting, Matthew W.

AU - Al-Obaidi, Nawar F.

AU - Lin, Henry

AU - O’Meara, Matthew J.

AU - Scott, David A.

AU - Morris, John H.

AU - Russel, Daniel

AU - Almo, Steven C.

AU - Osterman, Andrei L.

AU - Gerlt, John Alan

AU - Jacobson, Matthew P.

AU - Shoichet, Brian K.

AU - Sali, Andrej

PY - 2018/1/29

Y1 - 2018/1/29

N2 - The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology.

AB - The functions of most proteins are yet to be determined. The function of an enzyme is often defined by its interacting partners, including its substrate and product, and its role in larger metabolic networks. Here, we describe a computational method that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway. Given candidate enzyme and metabolite pathway members, this aim is achieved by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. We demonstrate this integrative pathway mapping method by predicting the L-gulonate catabolic pathway in Haemophilus influenzae Rd KW20. The prediction was subsequently validated experimentally by enzymology, crystallography, and metabolomics. Integrative pathway mapping by satisfaction of structural and network restraints is extensible to molecular networks in general and thus formally bridges the gap between structural biology and systems biology.

UR - http://www.scopus.com/inward/record.url?scp=85042106365&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042106365&partnerID=8YFLogxK

U2 - 10.7554/eLife.31097

DO - 10.7554/eLife.31097

M3 - Article

C2 - 29377793

AN - SCOPUS:85042106365

VL - 7

JO - eLife

JF - eLife

SN - 2050-084X

M1 - e31097

ER -