Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\25062272
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Biochemistry
2014 ; 53
(31
): 5111-20
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Nox4: a hydrogen peroxide-generating oxygen sensor
#MMPMID25062272
Nisimoto Y
; Diebold BA
; Cosentino-Gomes D
; Lambeth JD
Biochemistry
2014[Aug]; 53
(31
): 5111-20
PMID25062272
show ga
Nox4 is an oddity among members of the Nox family of NADPH oxidases [seven
isoenzymes that generate reactive oxygen species (ROS) from molecular oxygen] in
that it is constitutively active. All other Nox enzymes except for Nox4 require
upstream activators, either calcium or organizer/activator subunits (p47(phox),
NOXO1/p67(phox), and NOXA1). Nox4 may also be unusual as it reportedly releases
hydrogen peroxide (H?O?) in contrast to Nox1-Nox3 and Nox5, which release
superoxide, although this result is controversial in part because of possible
membrane compartmentalization of superoxide, which may prevent detection. Our
studies were undertaken (1) to identify the Nox4 ROS product using a
membrane-free, partially purified preparation of Nox4 and (2) to test the
hypothesis that Nox4 activity is acutely regulated not by activator proteins or
calcium, but by cellular pO?, allowing it to function as an O? sensor, the output
of which is signaling H?O?. We find that approximately 90% of the electron flux
through isolated Nox4 produces H?O? and 10% forms superoxide. The kinetic
mechanism of H?O? formation is consistent with a mechanism involving binding of
one oxygen molecule, which is then sequentially reduced by the heme in two
one-electron reduction steps first to form a bound superoxide intermediate and
then H?O?; kinetics are not consistent with a previously proposed internal
superoxide dismutation mechanism involving two oxygen binding/reduction steps for
each H?O? formed. Critically, Nox4 has an unusually high Km for oxygen (?18%),
similar to the values of known oxygen-sensing enzymes, compared with a Km of 2-3%
for Nox2, the phagocyte NADPH oxidase. This allows Nox4 to generate H?O? as a
function of oxygen concentration throughout a physiological range of pO2 values
and to respond rapidly to changes in pO?.
free
free
free
