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Gene Review

HMWP2  -  nonribosomal peptide synthetase

Yersinia pestis KIM10+

 
 
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Disease relevance of HMWP2

  • The pigmentation locus of Yersinia pestis KIM6+ is flanked by an insertion sequence and includes the structural genes for pesticin sensitivity and HMWP2 [1].
  • The 1-1382 fragment of HMWP2 (ArCP-Cy1-A), overproduced in Escherichia coli, contains the first three domains: the aryl carrier protein (ArCP) domain, the cysteine specific adenylation domain (A), and the first condensation/cyclization domain (Cy1) [2].
 

High impact information on HMWP2

  • The holo-NRPS module but not the holo-PKS module was then selectively aminoacylated with cysteine by the adenylation domain embedded in the HMWP2 subunit of yersiniabactin synthetase, acting in trans [3].
  • Yersiniabactin synthetase comprises four proteins, YbtE, HMWP1, HMWP2, and YbtU, encompassing seventeen functional domains, twelve catalytic and five carrier, to select, activate, and incorporate salicylate, three cysteines, and one malonyl moiety into the iron chelator yersiniabactin (Ybt) [4].
  • CONCLUSIONS: The HMWP1 and HMWP2 domain organization suggests that the yersiniabactin siderophore is assembled in a modular fashion, in which a series of covalent intermediates are passed from the amino terminus of HMWP2 to the carboxyl terminus of HMWP1 [5].
  • HMWP1 and HMWP2 also contain methyltransferase and heterocyclization domains [5].
  • The ybtD mutant failed to express indicator Ybt proteins (high-molecular-weight protein 1 [HMWP1], HMWP2, and Psn), a pattern similar to those seen with several other ybt biosynthetic mutants [6].
 

Chemical compound and disease context of HMWP2

  • Tandem heterocyclization activity of the multidomain 230 kDa HMWP2 subunit of Yersinia pestis yersiniabactin synthetase: interaction of the 1-1382 and 1383-2035 fragments [2].
  • The six-domain, 2035-amino acid subunit high-molecular weight protein 2 (HMWP2) activates salicylate and two cysteines and loads them covalently on its three carrier protein domains during assembly of the iron-chelating virulence factor, yersiniabactin of the plague bacterium Yersinia pestis [2].
 

Biological context of HMWP2

  • Expression, purification, and characterization of HMWP2, a 229 kDa, six domain protein subunit of Yersiniabactin synthetase [7].
  • The HMWP2 1383-2035 fragment contains the remaining three domains: two peptidyl carrier proteins (PCP1 and PCP2) separated by a second condensation/cyclization domain (Cy2) [2].
  • In contrast, cells containing a single amino acid substitution (S2908A) in the terminal thioesterase domain of HMWP2 failed to exhibit any ybt regulatory defects but did not elaborate extracellular Ybt under iron-deficient conditions [6].
  • The second step of A domain catalysis, capture of the bound aminoacyl adenylate by the P-pant-SH of the PCP domains, was assayed both by catalytic release of PP(i) and by covalent aminoacylation of radiolabeled substrates on either the PCP1 fragment of HMWP2 or the PCP3-thioesterase double domain fragment of HMWP1 [8].
  • The nonribosomal peptide synthetase HMWP2 forms a thiazoline ring during biogenesis of yersiniabactin, an iron-chelating virulence factor of Yersinia pestis [9].
 

Associations of HMWP2 with chemical compounds

  • Detection of the heterocyclization capacity of HMWP2 1-1491 implies salicyl-transferring and thiazoline-forming activity for the HMWP2 condensation domain (residues 101-544) and is the first demonstration of such heterocyclization ability in a nonribosomal peptide synthetase enzyme [9].
  • Phosphopantetheinylation of the HMWP2 1383-2035 fragment at Ser1439 (PCP1) and Ser1977 (PCP2) facilitates cysteinylation of both thiols by HMWP2 1-1382 [2].
 

Regulatory relationships of HMWP2

  • In addition, this strain as well as a Y. pestis strain with a mutation constructed in the gene (irp2) encoding the 190-kDa iron-regulated protein HMWP2 could not grow at 37 degrees C in a defined, iron-deficient medium [10].
  • HMWP2 likely participates in synthesis of a siderophore which may induce expression of the receptor for pesticin and the siderophore [10].
  • In contrast to Y. pestis, in which a psn mutation does not repress synthesis of Ybt siderophore or expression of the iron-regulated HMWP1 and HMWP2 proteins, the same mutation in Y. pseudotuberculosis partially repressed these products [11].
 

Other interactions of HMWP2

  • The irp2 gene, coding for a 190-kDa iron-regulated protein (HMWP2), and the hemin storage locus (hms), which determines Yersinia pestis pigmentation, are each located on a large chromosomal fragment which carries virulence genes and deletes spontaneously [12].

References

  1. The pigmentation locus of Yersinia pestis KIM6+ is flanked by an insertion sequence and includes the structural genes for pesticin sensitivity and HMWP2. Fetherston, J.D., Perry, R.D. Mol. Microbiol. (1994) [Pubmed]
  2. Tandem heterocyclization activity of the multidomain 230 kDa HMWP2 subunit of Yersinia pestis yersiniabactin synthetase: interaction of the 1-1382 and 1383-2035 fragments. Suo, Z., Walsh, C.T., Miller, D.A. Biochemistry (1999) [Pubmed]
  3. Purification, priming, and catalytic acylation of carrier protein domains in the polyketide synthase and nonribosomal peptidyl synthetase modules of the HMWP1 subunit of yersiniabactin synthetase. Suo, Z., Tseng, C.C., Walsh, C.T. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  4. Yersiniabactin synthetase: a four-protein assembly line producing the nonribosomal peptide/polyketide hybrid siderophore of Yersinia pestis. Miller, D.A., Luo, L., Hillson, N., Keating, T.A., Walsh, C.T. Chem. Biol. (2002) [Pubmed]
  5. Iron acquisition in plague: modular logic in enzymatic biogenesis of yersiniabactin by Yersinia pestis. Gehring, A.M., DeMoll, E., Fetherston, J.D., Mori, I., Mayhew, G.F., Blattner, F.R., Walsh, C.T., Perry, R.D. Chem. Biol. (1998) [Pubmed]
  6. Yersiniabactin production requires the thioesterase domain of HMWP2 and YbtD, a putative phosphopantetheinylate transferase. Bobrov, A.G., Geoffroy, V.A., Perry, R.D. Infect. Immun. (2002) [Pubmed]
  7. Expression, purification, and characterization of HMWP2, a 229 kDa, six domain protein subunit of Yersiniabactin synthetase. Keating, T.A., Miller, D.A., Walsh, C.T. Biochemistry (2000) [Pubmed]
  8. Selectivity of the yersiniabactin synthetase adenylation domain in the two-step process of amino acid activation and transfer to a holo-carrier protein domain. Keating, T.A., Suo, Z., Ehmann, D.E., Walsh, C.T. Biochemistry (2000) [Pubmed]
  9. The nonribosomal peptide synthetase HMWP2 forms a thiazoline ring during biogenesis of yersiniabactin, an iron-chelating virulence factor of Yersinia pestis. Gehring, A.M., Mori, I., Perry, R.D., Walsh, C.T. Biochemistry (1998) [Pubmed]
  10. Analysis of the pesticin receptor from Yersinia pestis: role in iron-deficient growth and possible regulation by its siderophore. Fetherston, J.D., Lillard, J.W., Perry, R.D. J. Bacteriol. (1995) [Pubmed]
  11. Yersiniabactin from Yersinia pestis: biochemical characterization of the siderophore and its role in iron transport and regulation. Perry, R.D., Balbo, P.B., Jones, H.A., Fetherston, J.D., DeMoll, E. Microbiology (Reading, Engl.) (1999) [Pubmed]
  12. Relationship between loss of pigmentation and deletion of the chromosomal iron-regulated irp2 gene in Yersinia pestis: evidence for separate but related events. Iteman, I., Guiyoule, A., de Almeida, A.M., Guilvout, I., Baranton, G., Carniel, E. Infect. Immun. (1993) [Pubmed]
 
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