TY - JOUR
T1 - Head-to-Head Prenyl Synthases in Pathogenic Bacteria
AU - Schwalen, Christopher J.
AU - Feng, Xinxin
AU - Liu, Weidong
AU - O-Dowd, Bing
AU - Ko, Tzu Ping
AU - Shin, Christopher J.
AU - Guo, Rey Ting
AU - Mitchell, Douglas A.
AU - Oldfield, Eric
N1 - This work was supported in part by an NIH Director's New Innovator Award (DP2 OD008463 to D.A.M.), the David and Lucile Packard Fellowship for Science and Engineering (to D.A.M.); the National Natural Science Foundation of China (grants 31200053, 31300615, 31400678, and 31470240); the Chinese Academy of Sciences (grant KSZD-EW-Z-015-2); the United States Public Health Service (NIH grants CA158191 and GM065307 to E.O.); a Harriet A. Harlin Professorship, and the University of Illinois Foundation/Oldfield Research Fund. C.J.S. is a member of the NIH Chemistry–Biology Interface Training Program (NRSA 1-T32 GM070421). We thank the National Synchrotron Radiation Research Center of Taiwan for beam time allocation and data collection assistance.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Many organisms contain head-to-head isoprenoid synthases; we investigated three such types of enzymes from the pathogens Neisseria meningitidis, Neisseria gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene, and we solved an inhibitor-bound structure that revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the first half of the reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis, we concluded that the Neisseria proteins were HpnDs (PSPP synthases). The differences in chemical reactivity to CrtM were due, at least in part, to the presence of a PSPP-stabilizing arginine in the HpnDs, decreasing the rate of dehydrosqualene biosynthesis. These results show that not only S. aureus but also other bacterial pathogens contain head-to-head prenyl synthases, although their biological functions remain to be elucidated.
AB - Many organisms contain head-to-head isoprenoid synthases; we investigated three such types of enzymes from the pathogens Neisseria meningitidis, Neisseria gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene, and we solved an inhibitor-bound structure that revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the first half of the reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis, we concluded that the Neisseria proteins were HpnDs (PSPP synthases). The differences in chemical reactivity to CrtM were due, at least in part, to the presence of a PSPP-stabilizing arginine in the HpnDs, decreasing the rate of dehydrosqualene biosynthesis. These results show that not only S. aureus but also other bacterial pathogens contain head-to-head prenyl synthases, although their biological functions remain to be elucidated.
KW - enzyme
KW - isoprenoid synthases
KW - meningitis
KW - squalene
KW - terpenes
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U2 - 10.1002/cbic.201700099
DO - 10.1002/cbic.201700099
M3 - Article
C2 - 28340291
AN - SCOPUS:85018837723
SN - 1439-4227
VL - 18
SP - 985
EP - 991
JO - ChemBioChem
JF - ChemBioChem
IS - 11
ER -