TY  - JOUR
AV  - public
ID  - heidok22344
SN  - 1471-2091
CY  - London; Berlin; Heidelberg
SP  - 1
N2  - Background: Nucleoside triphosphate (NTP) hydrolysis is a key reaction in biology. It involves breaking two very stable bonds (one P?O bond and one O?H bond of water), in either a concurrent or a sequential way. Here, we systematically examine how protonation of the triphosphate affects the mechanism of hydrolysis.   Results: The hydrolysis reaction of methyl triphosphate in vacuum is computed with protons in various numbers and position on the three phosphate groups. Protonation is seen to have a strong catalytic effect, with the reaction mechanism depending highly on the protonation pattern.   Conclusion: This dependence is apparently complicated, but is shown to obey a well-defined set of rules: Protonation of the ?- and ?-phosphate groups favors a sequential hydrolysis mechanism, whereas ?-protonation favors a concurrent mechanism, the two effects competing with each other in cases of simultaneous protonation. The rate-limiting step is always the breakup of the water molecule while it attacks the ?-phosphorus, and its barrier is lowered by ?-protonation. This step has significantly lower barriers in the sequential reactions, because the dissociated ?-metaphosphate intermediate (P?O3 ?) is a much better target for water attack than the un-dissociated ?-phosphate (?P?O4 2?). The simple chemical logic behind these rules helps to better understand the catalytic strategy used by NTPase enzymes, as illustrated here for the catalytic pocket of myosin. A set of rules was determined that describes how protonating the phosphate groups affects the hydrolysis mechanism of methyl triphosphate: Protonation of the ?- and/or ?- phosphate groups promotes a sequential mechanism in which P-O bond breaking precedes the breakup of the attacking water, whereas protonation of the ?-phosphate promotes a concurrent mechanism and lowers the rate-limiting barrier of water breakup. The role played by individual protein residues in the catalytic pocket of triphosphate hydrolysing enzymes can be assigned accordingly.
A1  - Kiani, Farooq Ahmad
A1  - Fischer, Stefan
Y1  - 2016///
IS  - 12
TI  - Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes
JF  - BMC Biochemistry
VL  - 17
EP  - 13
PB  - BioMed Central; Springer
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/22344/
ER  -