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3.3.2 Reactions with transition metals and metalloproteins
The biological chemistry of NO is strongly mediated through reaction with transition metals.
The reaction is with catalytic metal centres such as iron (Fe) in both haem and nonhaem
proteins (Tsai 1994). The high affinity of NO for the ferrous iron (Fe2+ in the reduced state) in
haemoglobin leads to a key interaction (Sharma, Traylor et al. 1987; Eich, Li et al. 1996). In
vivo, this reaction of NO and oxyhaemoglobin to form methaemoglobin and nitrate (NOl)
represents the major pathway for scavenging the endogenous NO production and is a
significant route of NO removal (Lancaster, Langrehr et al. lgg2). While this reaction is
rapid, in fact it would be too rapid to allow NO to interact with the subendothelial layer in the
vascular compartment (Lancaster, Langrehr et al. 1992). However, it is now known that when
the haemoglobin is in erythrocytes, the reaction with NO is limited by diffusion into the cell
and the half life is increased (Liu, Miller et al. 1998). Studies have shown that 70Vo ofthe NO
in humans is recovered as NO3- excreted through the urine (Westfelt, Benthin et al. 1995).
Oxyhaemoglobin can also directly oxidase NOz and NO3 forming methaemoglobin.
NO reaction with other Fe containing proteins can lead to either activation or inactivation
depending on the protein. For example, the reaction with soluble guanylyl cyclase (sGC) leads
to a conformational change which results in up to a 300 times increase in activation of the
enzyme. Activation of sCG results in the formation of cyclic quanosine monophosphate
(cGMP) from guanosine 5-triphosphate (GTp) (Ignarro, Degnan et al. l9g2) and accounts for
major signal transduction activity of NO. It is likely to be this mechanism that is the primary
one mediating vessel relaxation and the inhibition of platelet aggregation (Moncada and
Higgs l99l),In contrast, formation of a nitrosyl complex with cytochrome c oxidase leads to
reversible inhibition which is competitive with 02 binding @iserich, Patel et al. 1998).
NO also interacts with other metals such as zinc and copper. Formation of nitrosyl
compounds with co-ordinating cysteine residues results in release of zinc (Kroncke, Fehsel et
al. 1994). Formation of nitrosyl compounds with copper also occurs, and is particularly
important in copper containing enzymes such as the cytochrome c oxidase (Radi 1996). It is
through this type of interaction with metal ion containing proteins (metalloproteins) that NO
effects the enzymes of mitochondrial respiration and this is also a mechanism of the
macrophage mediated defence and involves, for example, cytochrome c oxidase and catalases
(Cleeter, Cooper et al. 1994; Torres, Darley-Usmar et al. 1995). Part of this is an NO and Oz
competition at the cytochrome c oxidase binding site for 02 and therefore NO inhibition is
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