Mechanistic Insights into the Activation of Soluble
Guanylate Cyclase by Carbon Monoxide: A Multistep Mechanism Proposed
for the BAY 41-2272 Induced Formation of 5‑Coordinate CO–Heme
Version 2 2018-02-20, 21:07
Version 1 2018-02-20, 21:05
Posted on 2018-02-20 - 21:07
Soluble
guanylate cyclase (sGC) is a heme-containing enzyme that
catalyzes cGMP production upon sensing NO. While the CO adduct, sGC–CO,
is much less active, the allosteric regulator BAY 41-2272 stimulates
the cGMP productivity to the same extent as that of sGC–NO.
The stimulatory effect has been thought to be likely associated with
Fe-His bond cleavage leading to 5-coordinate CO–heme, but the
detailed mechanism remains unresolved. In this study, we examined
the mechanism under the condition including BAY 41-2272, 2′-deoxy-3′-GMP
and foscarnet. The addition of these effectors caused the original
6-coordinate CO–heme to convert to an end product that was
an equimolar mixture of a 5- and a new 6-coordinate CO–heme,
as assessed by IR spectral measurements. The two types of CO–hemes
in the end product were further confirmed by CO dissociation kinetics.
Stopped-flow measurements under the condition indicated that the ferrous
sGC bound CO as two reversible steps, where the primary step was assigned
to the full conversion of the ferrous enzyme to the 6-coordinate CO–heme,
and subsequently followed by the slower second step leading a partial
conversion of the 6-coordinate CO–heme to the 5-coordinate
CO–heme. The observed rates for both steps linearly depended
on CO concentrations. The unexpected CO dependence of the rates in
the second step supports a multistep mechanism, in which the 5-coordinate
CO–heme is led by CO release from a putative bis-carbonyl intermediate
that is likely provided by the binding of a second CO to the 6-coordinate
CO–heme. This mechanism provides a new aspect on the activation
of sGC by CO.
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Makino, Ryu; Obata, Yuji; Tsubaki, Motonari; Iizuka, Tetsutaro; Hamajima, Yuki; Kato-Yamada, Yasuyuki; et al. (2018). Mechanistic Insights into the Activation of Soluble
Guanylate Cyclase by Carbon Monoxide: A Multistep Mechanism Proposed
for the BAY 41-2272 Induced Formation of 5‑Coordinate CO–Heme. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.7b01240
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AUTHORS (8)
RM
Ryu Makino
YO
Yuji Obata
MT
Motonari Tsubaki
TI
Tetsutaro Iizuka
YH
Yuki Hamajima
YK
Yasuyuki Kato-Yamada
KM
Keisuke Mashima
YS
Yoshitsugu Shiro