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  • Review Article
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Control of key metabolic intersections in Bacillus subtilis

Nature Reviews Microbiology volume 5, pages 917–927 (2007)Cite this article

Key Points

  • Bacteria adapt readily to many different nutritional environments by altering gene expression in accordance with the availability of particular nutrients. Each metabolic gene or operon is regulated by specific factors that sense the intracellular concentrations of substrates for degradation or the end-products of biosynthesis.

  • Overlying this operon-specific regulation are at least two additional levels of regulation. The first coordinates the expression of groups of operons according to their general function (for example, the use of carbon souces). The second coordinates the expression of large groups of genes according to their impact on the overall balance of central metabolism.

  • In Bacillus subtilis, three global regulatory proteins mediate both function- and metabolism-coordinating gene expression. CcpA and TnrA are the global regulators for carbon metabolism and nitrogen metabolism, respectively, and part of their function is to influence the activity of a third global regulator, CodY.

  • If glucose is available, B. subtilis CodY functions in conjunction with CcpA to repress the use of alternative carbon sources and activate the expression of carbon-overflow pathways.

  • If cells are in a rich medium, CodY also represses the use of alternative nitrogen sources; if the cell has to depend on poor nitrogen sources, repression by CodY is relieved, but at the same time positive regulation of the same genes by TnrA is activated.

  • The activity of CodY as a DNA-binding protein is greatly stimulated by two types of ligands — GTP and the branched-chain amino acids. Both CcpA and TnrA regulate the synthesis of these amino acids, thereby helping to determine the extent to which CodY is active. A fourth global regulatory system, the stringent response to amino-acid deprivation, leads to a drop in the intracellular GTP pool and, therefore, also influences the activity of CodY.

  • In some Gram-positive pathogens, CcpA and CodY proteins control virulence genes as well as metabolism genes, which connects the expression of virulence to the metabolic state of the cell.

Abstract

The remarkable ability of bacteria to adapt efficiently to a wide range of nutritional environments reflects their use of overlapping regulatory systems that link gene expression to intracellular pools of a small number of key metabolites. By integrating the activities of global regulators, such as CcpA, CodY and TnrA, Bacillus subtilis manages traffic through two metabolic intersections that determine the flow of carbon and nitrogen to and from crucial metabolites, such as pyruvate, 2-oxoglutarate and glutamate. Here, the latest knowledge on the control of these key intersections in B. subtilis is reviewed.

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Figure 1: Interactions of the global regulators CcpA and CodY with carbon-overflow metabolism in Bacillus subtilis.
Figure 2: Interactions of global regulators with the citric acid cycle in Bacillus subtilis.
Figure 3: Bacillus subtilis global regulators at the intersection between carbon and nitrogen metabolism.
Figure 4: The metabolic context of the Bacillus subtilis branched-chain amino acid biosynthetic pathway.
Figure 5: Intersection of RelA, CcpA and CodY in the regulation of the Bacillus subtilis ilvB operon.

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Acknowledgements

The author thanks the anonymous reviewers for many helpful suggestions. The unpublished work cited in this Review was supported by research grants from the US Public Health Service (GM042219, GM036718 and AI057637).

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  1. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, 02111, Massachusetts, USA

    Abraham L. Sonenshein

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DATABASES

Entrez Genome Project

Bacillus anthracis

Bacillus subtilis

Clostridium difficile

Clostridium perfringens

Escherichia coli

Lactococcus lactis

Listeria monocytogenes

Staphylococcus aureus

Staphylococcus xylosus

Streptococcus pneumoniae

Streptococcus pyogenes

Entrez Protein

CcpA

CcpC

CodY

Crh

GltC

HPr

pppGpp

RocG

RocR

TnrA

FURTHER INFORMATION

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Glossary

Glycolysis

The metabolic pathway that converts glucose into pyruvate, with the concomitant production of ATP and NADH.

Pentose-phosphate pathway

The metabolic pathway by which glucose-6-phosphate is oxidized to ribose-5-phosphate, with the concomitant production of NADPH.

Citric acid cycle

The metabolic pathway that oxidizes acetyl CoA to carbon dioxide.

2-oxoglutarate–glutamate–glutamine cycle

The metabolic pathway that connects carbon and nitrogen metabolism and permits ammonium ions to be incorporated into organic molecules.

Global regulator

A protein that controls many genes and operons in response to a specific signal.

Sporulation

A developmental programme in some microorganisms in response to unfavourable environmental conditions that results in spores that are highly resistant to environmental stresses.

LacI protein family

The proteins that are related in sequence and function to the classical repressor of the E. coli lac operon.

Phosphoenolpyruvate-dependent phosphotransferase transport system

A multi-protein phosphorelay system that couples the phosphorylation of sugars to their transport across the cytoplasmic membrane.

Competence

The ability of bacteria to take up extracellular DNA.

Homolactic fermentation

The production of lactic acid (lactate) as the sole pyruvate-derived product during growth on sugars, such as glucose.

Two-component regulatory system

A system that responds to an environmental stimulus and regulates gene expression accordingly. Composed of a histidine-kinase sensor, usually situated in the outer membrane, that phosphorylates a response regulator in the cytoplasm, which, in turn, activates transcription from selected promoters.

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Sonenshein, A. Control of key metabolic intersections in Bacillus subtilis. Nat Rev Microbiol 5, 917–927 (2007). https://doi.org/10.1038/nrmicro1772

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