Genome-scale reconstruction of the metabolic network in Yersinia pestis, strain 91001

Abstract

The gram-negative bacterium Yersinia pestis, the aetiological agent of bubonic plague, is one of the deadliest pathogens known to man. Despite its historical reputation, plague is a modern disease which annually afflicts thousands of people. Public safety considerations greatly limit clinical experimentation on this organism and thus development of theoretical tools to analyze the capabilities of this pathogen is of utmost importance. Here, we report the first genome-scale metabolic model of Yersinia pestis biovar Mediaevalis based both on its recently annotated genome, and physiological and biochemical data from the literature. Our model demonstrates excellent agreement with Y. pestis' known metabolic needs and capabilities. Since Y. pestis is a meiotrophic organism, we have developed CryptFind, a systematic approach to identify all candidate cryptic genes responsible for known and theoretical meiotrophic phenomena. In addition to uncovering every known cryptic gene for Y. pestis, our analysis of the rhamnose fermentation pathway suggests that betB is the responsible cryptic gene. Despite all of our medical advances, we still do not have a vaccine for bubonic plague. Recent discoveries of antibiotic resistant strains of Yersinia pestis coupled with the threat of plague being used as a bioterrorism weapon compel us to develop new tools for studying the physiology of this deadly pathogen. Using our theoretical model, we can study the cell's phenotypic behavior under different circumstances and identify metabolic weaknesses that may be harnessed for the development of therapeutics. Additionally, the automatic identification of cryptic genes expands the usage of genomic data for pharmaceutical purposes.

Evolutionary Dynamics of the Yersinia enterocolitica Complex

“…Rare rhamnose-positive mutants are observed in Y. pestis after prolonged incubation (Englesberg, 1957a,b). The rhamnose operon rhaTRSBAD is present in all Y. pestis, and BetB, a betaine-aldehyde dehydrogenase, and RhaS, a transcriptional regulator, have been suggested as the genetic basis for this phenotype (Navid and Almaas, 2009;Eppinger, et al, 2010). This ability of Y. pestis for phenotypic gain of function is known as meiotrophy, and has also been documented for ammonia assimilation, urease, production of inv, fermentation of melibiose, and biosynthesis of certain amino acids (Brubaker, 1991).…”

“…It is referred to as the "hare-biotype", and has not been isolated from humans (Swaminathan, Harmon and Mehlman, 1982;Wuthe and Aleksic, 1997;Bartling, et al, 2004 (Burrows and Gillett, 1966;Perry and Fetherston, 1997;Navid and Almaas, 2009). This is due to the biphasic lifecycle of Y. pestis, being present either in a warm-blooded host or in the flea.…”

“…This is due to the biphasic lifecycle of Y. pestis, being present either in a warm-blooded host or in the flea. Y. pestis is not subjected to environmental metabolic challenges, and at the same time the bacterium depends on the host to provide for nutrients (Navid and Almaas, 2009). In contrast to the biotyping scheme, the phenotypic micorarray also highlighted some nitrogen, phosphorus, and sulphur sources that are absent from BT 1A.…”

Inferring ancient metabolism using ancestral core metabolic models of enterobacteria

“…To date, GEMs of enterobacteria have been constructed for three standard laboratory E. coli strains [4,6-8,10], four pathogenic E. coli strains [4], one Salmonella strain [14,16], one Klebsiella strain [12], two Yersinia strains [10,13], and one insect endosymbiont, Buchnera [15]. These GEMs have been used to bioengineer strains for valuable end product formation [17-22], to conduct simulations to investigate metabolic processes during host-pathogen interactions [14], to identify differentiating metabolic properties between commensal and pathogenic E. coli strains [4], and to provide insight into the genome evolution of other enterobacteria [23-25].…”

Structure and Function of the d -Galactose Network in Enterobacteria

“…Changes can affect the elements (e.g., genes) of the network as well as the interactions in the network. Redundant genes or those that antagonize successful colonization in the new environment can be inactivated by point mutations or removed by deletions (1). Also, genes required for adaptation to a new niche can be acquired by horizontal transfer (e.g., pathogenicity islands) (2).…”