Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

Barta, Michael L.; Thomas, Keisha; Yuan, Hongling; Lovell, Scott; Battaile, Kevin P.; Schramm, Vern L.; Hefty, P. Scott

doi:10.1074/jbc.m114.594325

Cited by 18 publications

(23 citation statements)

References 69 publications

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“…The chlamydial oxidative phosphorylation system consists of the sodium-dependent NADH dehydrogenase (Na ϩ -NQR), succinate dehydrogenase, cytochrome bd oxidase, and an A 1 -A 0 -ATPase (12,24,25). Furthermore, C. trachomatis seems to use menaquinone (26), instead of ubiquinone, which is used by mitochondria (27). Na ϩ -NQR is a unique respiratory complex that is analogous to the mitochondrial complex I, incorporating the electrons from NADH into ubiquinone, feeding the lower part of the respiratory chain (28).…”

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confidence: 99%

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

Liang

Rosas‐Lemus²,

Patel

et al. 2018

Journal of Biological Chemistry

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is an obligate intracellular human pathogen responsible for the most prevalent sexually-transmitted infection in the world. For decades has been considered an "energy parasite" that relies entirely on the uptake of ATP from the host cell. The genomic data suggest that respiratory chain could produce a sodium gradient that may sustain the energetic demands required for its rapid multiplication. However, this mechanism awaits experimental confirmation. Moreover, the relationship of chlamydiae with the host cell, in particular its energy dependence, is not well understood. In this work, we are showing that has an active respiratory metabolism that seems to be coupled to the sodium-dependent synthesis of ATP. Moreover, our results show that the inhibition of mitochondrial ATP synthesis at an early stage decreases the rate of infection and the chlamydial inclusion size. In contrast, the inhibition of the chlamydial respiratory chain at mid-stage of the infection cycle decreases the inclusion size but has no effect on infection rate. Remarkably, the addition of monensin, a Na/H exchanger, completely halts the infection. Altogether, our data indicate that chlamydial development has a dynamic relationship with the mitochondrial metabolism of the host, in which the bacterium mostly depends on host ATP synthesis at an early stage, and at later stages it can sustain its own energy needs through the formation of a sodium gradient.

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confidence: 99%

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

Liang

Rosas‐Lemus²,

Patel

et al. 2018

Journal of Biological Chemistry

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“…Later, the experimental work provided the evidence that the protein CT398(cdsZ) interacted with σ(54) (RpoN)-holoenzyme and the type-III secretion export apparatus in C. trachomatis [64]. Hypothetical protein CT263, with structural similarity to 5′-methylthioadenosine nucleosidase enzymes, supports the evidence that menaquinone synthesis in Chlamydiaceae is mediated through futalosine pathway [62]. A chromosomally encoded hypothetical protein TC0668 was found to serve as an important chromosome-encoded genitourinary pathogenicity factor in C. muridarum [65].…”

Section: Discussionmentioning

confidence: 94%

In Silico Functional Elucidation of Uncharacterized Proteins of Chlamydia Abortus Strain LLG

et al. 2017

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Aim:This study reports structural modeling, molecular dynamics profiling of hypothetical proteins in Chlamydia abortus genome database.Methodology:The hypothetical protein sequences were extracted from C. abortus LLG Genome Database for functional elucidation using in silico methods.Results:Fifty-one proteins with their roles in defense, binding and transporting other biomolecules were unraveled. Forty-five proteins were found to be nonhomologous to proteins present in hosts infected by C. abortus. Of these, 31 proteins were related to virulence. The structural modeling of two proteins, first, WP_006344020.1 (phosphorylase) and second, WP_006344325.1 (chlamydial protease/proteasome-like activity factor) were accomplished. The conserved active sites necessary for the catalytic function were analyzed.Conclusion:The finally concluded proteins are envisioned as possible targets for developing drugs to curtail chlamydial infections, however, and should be validated by molecular biological methods.

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“…This would explain the activity I observed in the peptide oxidation assay where endogenous E. coli UQ is used, and the lack of activity in the gel shift assay where UQ-1 was used. Although a potential UQ biosynthesis pathway has been identified in C. trachomatis [233,234] the side-chain length of UQ has not been determined. To investigate whether the lack of CtDsbB catalysed oxidation 97 of CtDsbA is due to the inability of UQ-1 to act as electron acceptor for CtDsbB, different UQ molecules should be screened.…”

Section: Uq Binding Diverting From Ecdsbb Might Influence Ctdsbb Catamentioning

confidence: 99%

“…Gram-negative and Gram-positive bacteria rely on MK entirely [234,235]. Genomic sequencing of C. trachomatis identified four enzymes common to UQ and MK biosynthesis pathways [233].…”

Section: Uq Binding Diverting From Ecdsbb Might Influence Ctdsbb Catamentioning

confidence: 99%

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The disulfide oxidative pathway in Chlamydia trachomatis

Christensen¹

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The disulfide oxidative pathway in bacteria is responsible for disulfide bond formation in secreted proteins including many virulence factors. The archetypal Escherichia coli DsbA and DsbB enzymes form a redox relay that catalyses disulfide bond formation and constitutes the oxidative folding pathway. DsbA orthologs from a broad range of bacteria have been characterised and while the enzymes have similar structural and biochemical characteristics they vary in redox chemistry and surface properties. An overview of the DsbA and DsbB enzymes from different bacteria is provided in Chapter 1. Chapter 1 also provides an overview of antibiotics with well-known and novel targets, including bacterial oxidative folding.Chlamydia trachomatis is an obligate intracellular pathogen responsible for blinding trachoma and the sexually transmitted infection chlamydia that can lead to infertility and ectopic pregnancy. C. trachomatis has a biphasic developmental cycle that is dependent on coordinated disulfide bond formation and reduction for differentiation between the two distinct cell types: reticular body (RB) and elementary body (EB) (reviewed in chapter 1).Chapter 2 presents a biochemical and structural characterisation of a truncated soluble form of DsbA from C. trachomatis (CtDsbA), which was published in PLOS ONE. CtDsbA is the first structurally characterised DsbA having two small, uncharged amino acids separating the two active site cysteines (Cys-Ser-Ala-Cys). Characterisation of CtDsbA shows that is has oxidase activity and is structurally similar to other DsbAs. However, CtDsbA is distinct in that it is the weakest oxidising DsbA so far described. This is consistent with the analysis of the 2.7 Å resolution crystal structure showing a lack of factors stabilising the nucleophilic thiolate anion of Cys38. CtDsbA is also distinguished from most other DsbAs by having a disulfide bond, linking helix 2 and helix 5, that has only been reported in three other structurally characterised DsbAs, including Wolbachia pipientis DsbA1 (WpDsbA1).Chapter 3 describes my studies of the interaction between CtDsbA and CtDsbB. In the oxidative pathway of E. coli, DsbA (EcDsbA) is kept in its active, oxidised state by the integral membrane protein DsbB (EcDsbB) in a mechanism dependent on a quinone cofactor. A BLAST search identified a protein (CtDsbB) in the genome of C. trachomatis with 21% sequence identity to EcDsbB and a predicted secondary structure topology equivalent to EcDsbB. Chapter 3 presents the characterisation of the interaction between CtDsbA and CtDsbB showing that crude membranes containing heterogeneously expressed CtDsbB are able to oxidize CtDsbA. However, purified, detergent solubilised CtDsbB is not able to oxidise CtDsbA in the presence of ubiquinone-1 suggesting that purified CtDsbB is inactive in detergent micelles or that ubiquinone-1 is not a suitable cofactor for CtDsbB. In contrast to what was found for Wolbachia DsbA1, the non-catalytic disulfide of CtDsbA does not regulate interaction with CtDsbB. Interesting...

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Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

Cited by 18 publications

References 69 publications

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

Dynamic energy dependency of Chlamydia trachomatis on host cell metabolism during intracellular growth: Role of sodium-based energetics in chlamydial ATP generation

In Silico Functional Elucidation of Uncharacterized Proteins of Chlamydia Abortus Strain LLG

The disulfide oxidative pathway in Chlamydia trachomatis

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