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Encyclopedia of Physical Science and Technology EN002F-55 May 22, 2001 21:6

132 Bioinorganic Chemistry

the other contains two manganese atoms. The heme- Another medically important enzyme, nitric oxide syn-
containing catalases have a tyrosine bound to the iron in thase (NOS), has many similarities to cyts P450 and cat-
the heme. In the reduced state, the iron is in the +3 ox- alyzes the formation of nitric oxide. Nitric oxide is a
idation state. During the reduction of peroxide to water, messenger involved in vasodilation and inflammatory re-
the porphyrin and iron are each oxidized by one electron sponse. The production of nitric oxide is a result of the
+
forming a (porphyrin )Fe(IV) O. This species, known as degradation of the amino acid arginine. Like cytochrome
Compound I, can oxidize a second hydrogen peroxide to P450, the active center is a heme and the reaction is
oxygen, completing the catalytic cycle. The manganese NAD(P)H dependent. Unlike cytochrome P450s, the cur-
catalases, which are far less common than their heme rent view on the mechanism of NO production does not
+
counterparts, contain a manganese dimer where both man- involve por Fe IV O. Instead, the reactive species is
2+
−
ganese atoms cycle between +2 and +3 oxidation states believed to be porFe III OO . NOS is mediated by Ca –
during catalysis. calmodulin and does not produce nitric oxide in the ab-
sence of calcium.
G. Chemical Transformation
In the section on respiration above, it was shown how H. Nitrogen Fixation
oxygen reduction to water is used as the engine to produce
Nitrogen fixation is the most important reaction of the
ATP. Oxygen is also used in the body as a substrate to carry
biological nitrogen cycle. The presence of nitrogen in
out chemical transformations. Oxygenases are enzymes
molecules other than N 2 is frequently the limiting plant
that activate oxygen for insertion into organic molecules.
growth requirement. The six-electron reduction of the
One class of oxygenases are the cytochromes P450 (cyts
N≡N bond to form ammonia is ultimately favorable and
P450). Cyts P450 catalyze the NADH (or NADPH) as-
gives off a significant amount of energy:
sisted oxidation of organic molecules:
+
O 2 + R H + NAD(P)H −→ R OH + H 2 O + NAD(P) . N 2 + 6H + 6e −→ 2NH 3 . (8)
+
−
(7)
However, in the Born–Haber process, the commercial pro-
II
A heme group, porFe , is attached to the protein through duction of ammonia, the formation of the partially reduced
a single iron–cysteine interaction leaving an open coordi- intermediates requires high temperature and pressure. Re-
nation site on the iron to bind oxygen. During catalysis, markably, by acquiring energy from ATP hydrolysis and
the substrate, R H, is bound in the active site close to coupling the reaction with hydrogen (H 2 ) formation,
the iron heme. The iron then binds oxygen and reduces
it with help from NADH or NADPH. During this reduc- N 2 + 16H 2 O + 16ATP + 8e −
tion, one molecule of water is released and an iron oxo
V
IV
+
+
complex (porFe O or por Fe O) is formed. This iron −→ 2NH 3 + H 2 + 16ADP + 16P i + 8H , (9)
oxo species is reduced upon reaction with the substrate to
III
produce ROH and porFe . The iron can be reduced by a microbes are able to convert N 2 to NH 3 at room temper-
1 NAD(P)H to return to its initial state, porFe . Using a ature and pressure. In this way, nature has been able to
II
2
heme group, cyts P450 are involved in drug, hormone, and stabilize the necessary intermediates to carry out the req-
cell wall metabolism and other biosynthetic reactions. uisitechemistry.Theenzymenitrogenasereducesnitrogen
The mode of action of azole antifungal agents is bind- by employing two separate proteins. One of the proteins,
ing to cytP450 to block the conversion of ergosterol to the FeMo protein, contains two large cofactors (FeMoCo
lanosterol. The depletion of lanosterol causes severe cell containing seven irons, nine sulfurs, one molybdenum,
membrane disruption in the fungi. The cyts P450 are also and homocitrate, and P clusters with eight iron atoms
essential for the metabolism of many common drugs such and seven sulfurs). The other, smaller protein contains an
as theophyllen, erythromycin, warfarin, and verapamil. iron–sulfur cluster and is termed the Fe protein. Although
Many isozymes, for example, cyt P450 3A/4, are found both enzymes need to be present for catalysis, the loca-
in the human liver; however, several of these are known tion of nitrogen reduction is the FeMoCo site in the FeMo
to metabolize, be inhibited by, or be induced by multiple protein. Electrons are transferred to the FeMo protein by
common pharmaceuticals. Hence, evaluation of drug in- the Fe protein. The process is driven by ATP hydrolysis.
teractions with cytP450 is an important issue in modern The molecular mechanism by which this occurs is under
pharmaceutical therapies. investigation.