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Cited by 26Porphyrin Metabolism and DisordersPorphyrin and Phthalocyanine ChemistryBiochemical and Molecular Research

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Inhibition of Escherichia coli porphobilinogen synthase using analogs of postulated intermediates

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Jarret, Caroline, Stauffer, Frédéric, Henz, Matthias E, Marty, Maurus, Lüönd, Rainer M, Bobálová, Janette, Schürmann, Peter, Neier, Reinhard·2000·Chemistry & Biology
DOI 10.1016/s1074-5521(00)00089-2
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Abstract

Background Porphobilinogen synthase is the second enzyme involved in the biosynthesis of natural tetrapyrrolic compounds, and condenses two molecules of 5-aminolevulinic acid (ALA) through a nonsymmetrical pathway to form porphobilinogen. Each substrate is recognized individually at two different active site positions to be regioselectively introduced into the product. According to pulse-labeling experiments, the substrate forming the propionic acid sidechain of porphobilinogen is recognized first. Two different mechanisms for the first bond-forming step between the two substrates have been proposed. The first involves carbon-carbon bond formation (an aldol-type reaction) and the second carbon-nitrogen bond formation, leading to an iminium ion. Results With the help of kinetic studies, we determined the Michaelis constants for each substrate recognition site. These results explain the Michaelis-Menten behavior of substrate analog inhibitors - they act as competitive inhibitors. Under standard conditions, however, another set of inhibitors demonstrates uncompetitive, mixed, pure irreversible, slow-binding or even quasi-irreversible inhibition behavior. Conclusions Analysis of the different classes of inhibition behavior allowed us to make a correlation between the type of inhibition and a specific site of interaction. Analyzing the inhibition behavior of analogs of postulated intermediates strongly suggests that carbon-nitrogen bond formation occurs first.

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Metadata

Authors
Jarret, C., Stauffer, F., Henz, M. E., Marty, M., Lüönd, R. M., Bobálová, J., Schürmann, P., & Neier, R.
Affiliations
University of Neuchâtel (CH)
Corresponding author
Neier, Reinhard
ORCID
Venue
Chemistry & Biology
Publisher
Elsevier BV
Published
2000-03
Volume
7
Issue
3
Pages
185-196
ISSN
1074-5521 (ISSN-L)
DOI
10.1016/s1074-5521(00)00089-2
OpenAlex
W2043638626
Cited by
26
References
60
Citations by year
2021: 1 · 2017: 1 · 2015: 2 · 2012: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Chemistry & Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
  • Physical Sciences › Materials Science › Materials Chemistry › Porphyrin and Phthalocyanine Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
delta-aminolevulinic acid dehydratase, Escherichia coli, 5-aminolevulinic acid, tetrapyrrole biosynthesis, substrate analog inhibitors, enzyme inhibition kinetics, Michaelis-Menten kinetics, competitive inhibition, uncompetitive inhibition, mixed-type inhibition, irreversible inhibition, slow-binding inhibition, C–N bond formation, iminium ion intermediate, substrate recognition site, regioselectivity
MeSH terms
Aminolevulinic Acid, Porphobilinogen Synthase, Binding, Competitive, Dicarboxylic Acids, Enzyme Inhibitors, Escherichia coli, Kinetics, Models, Chemical, Porphobilinogen, Structure-Activity Relationship, Substrate Specificity, Catalytic Domain

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CoChat. (2026). Citation check: Inhibition of Escherichia coli porphobilinogen synthase using analogs of postulated intermediates. https://app.cochat.ai/papers/10.1016/s1074-5521(00)00089-2
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Jarret, C., Stauffer, F., Henz, M. E., Marty, M., Lüönd, R. M., Bobálová, J., Schürmann, P., & Neier, R. (2000). Inhibition of Escherichia coli porphobilinogen synthase using analogs of postulated intermediates. Chemistry & Biology. https://doi.org/10.1016/s1074-5521(00)00089-2