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Title: Conservation of the structure and function of bacterial tryptophan synthases

Journal Article · · IUCrJ
 [1];  [2];  [3]; ORCiD logo [1];  [4];  [1];  [2];  [3];  [2];  [1]; ORCiD logo [2];  [2];  [2];  [2];  [3];  [5]
  1. Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; Argonne National Lab. (ANL), Argonne, IL (United States). Bioscience Division
  2. Broad Institute of MIT and Harvard, Cambridge, MA (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States). Bioscience Division
  4. Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases
  5. Univ. of Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases, and Dept. of Biochemistry and Molecular Biology; Argonne National Lab. (ANL), Argonne, IL (United States). Bioscience Division
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Tryptophan biosynthesis is one of the most characterized processes in bacteria, in which the enzymes fromSalmonella typhimuriumandEscherichia coliserve as model systems. Tryptophan synthase (TrpAB) catalyzes the final two steps of tryptophan biosynthesis in plants, fungi and bacteria. This pyridoxal 5'-phosphate (PLP)-dependent enzyme consists of two protein chains, α (TrpA) and β (TrpB), functioning as a linear αββα heterotetrameric complex containing two TrpAB units. The reaction has a complicated, multistep mechanism resulting in the β-replacement of the hydroxyl group of L-serine with an indole moiety. Recent studies have shown that functional TrpAB is required for the survival of pathogenic bacteria in macrophages and for evading host defense. Therefore, TrpAB is a promising target for drug discovery, as its orthologs include enzymes from the important human pathogensStreptococcus pneumoniae,Legionella pneumophilaandFrancisella tularensis, the causative agents of pneumonia, legionnaires' disease and tularemia, respectively. However, specific biochemical and structural properties of the TrpABs from these organisms have not been investigated. To fill the important phylogenetic gaps in the understanding of TrpABs and to uncover unique features of TrpAB orthologs to spearhead future drug-discovery efforts, the TrpABs fromL. pneumophila,F. tularensisandS. pneumoniaehave been characterized. In addition to kinetic properties and inhibitor-sensitivity data, structural information gathered using X-ray crystallography is presented. The enzymes show remarkable structural conservation, but at the same time display local differences in both their catalytic and allosteric sites that may be responsible for the observed differences in catalysis and inhibitor binding. This functional dissimilarity may be exploited in the design of species-specific enzyme inhibitors.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1560154
Journal Information:
IUCrJ, Vol. 6, Issue 4; ISSN 2052-2525
Publisher:
International Union of CrystallographyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 11 works
Citation information provided by
Web of Science

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Cited By (1)

Allosteric inhibitors of Mycobacterium tuberculosis tryptophan synthase journal January 2020

Figures / Tables (10)

Table 1(p. 21)table Table 1
Table 2(p. 22)table Table 2
Figure 1(p. 23)figure Figure 1
Figure 2(p. 24)figure Figure 2
Figure 3(p. 25)figure Figure 3
Figure 4(p. 26)figure Figure 4
Figure 5(p. 27)figure Figure 5
Figure 6(p. 28)figure Figure 6
Figure 7(p. 29)figure Figure 7
Figure 8(p. 30)figure Figure 8

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Francisella tularensis
Legionella pneumophila
Streptococcus pneumoniae
X-ray crystallography
allosteric regulation
catalysis
crystal structure
drug discovery
enzyme inhibitors
enzyme mechanisms
molecular recognition
protein structure
structure determination
tryptophan
tryptophan synthase