Cytochrome P450
stuck even though cytochromes P450,
defnition oF cytochromes. Subsequently,
the pigment in question was shown
prosthetic group Found associated with
many other hemoproteins, most notably
hemoglobin and myoglobin. Hemoglobin
and myoglobin also show an intense
absorbance upon reduction and binding to
CO, but with these proteins the maximum
is at 420 nm. Iron has six coordination
positions: Four coordination positions in
protoheme are occupied by the pyrrole
nitrogens; in hemoglobin and myoglobin,
the fFth coordination position is provided
by the imidazole group oF the proximal
histidine; and the sixth position is available
to bind gaseous ligands such as O
CO. It is now apparent that in P450s,
the fFth coordination position is provided
by a thiolate group From the amino
acid cysteine. Although the Nomenclature
Committee oF the International Union oF
Biochemistry suggests the name ‘‘heme-
thiolate protein’’ rather than ‘‘cytochrome
P450,’’ common usage in the feld is
simply P450, dropping the ‘‘cytochrome.’’
Shortly aFter Sato and Omura tagged this
hemoprotein as cytochrome P450, Ronald
Estabrook, Otto Rosenthal, and David
Cooper at the University oF Pennsylvania
assigned a Function to a cytochrome
P450 in the endoplasmic reticulum oF
the adrenal cortex by demonstrating with
CO inhibition and photochemical action
spectroscopy its ability to
progesterone at C-21. We now know that
there are many diFFerent P450s and that
they catalyze the general reaction type
shown above.
Returning to our analogy with hemoglo-
bin, we recognize that a Fundamental
diFFerence between P450 and hemoglobin
is that hemoglobin binds O
and transports it unchanged, while P450
reduces O
, one atom oF oxygen being in-
serted into the substrate and the other
used For the Formation oF water. The
redox potentials oF these two hemopro-
teins are quite diFFerent, that oF P450
300 mV or lower, while that oF
hemoglobin is
110 mV. Presumably, the
electron-donating capacity oF the thiolate
ligand can Facilitate the reduction oF O
making P450s potent monooxygenases.
Not all heme-thiolate proteins are P450s,
but we will fnd that P450s consist oF a
very large number oF proteins (over 2,400
identifed to date) Found in plants, bacte-
ria, birds, fshes, insects, mammals, and
probably all other Forms oF liFe.
±or the heme iron to reduce oxygen,
cytochrome P450 must receive electrons
From reduced pyridine nucleotides (ei-
ther NADH or NADPH) via an electron
transport system. In bacteria, P450s are
soluble proteins; in plants, insects, and an-
imals, they reside as integral members
oF subcellular membranes. Virtually all
soluble bacterial P450s, as well as those
Forms localized in mitochondrial mem-
branes oF eukaryotes, receive electrons via
the Following pathway:
(±AD – containing)
(oFten 2±e-2S)
Electrons are transFerred to the P450 one
at a time From the Ferredoxin. In mito-
chondria, P450s are localized to the inner
mitochondrial membrane, with Ferredoxin
reductase and Ferredoxin residing as solu-
ble proteins in the matrix. In eukaryotes,
the majority oF P450s are localized in the
endoplasmic reticulum as integral mem-
brane proteins. Reducing equivalents are
transFerred to these P450s via a micro-
somal flavoprotein quite distinct From
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