Other Iron-containing Proteins

FIGURE 13.20 Reactions catalysed by each of the five families of mononuclear nonhaem iron enzymes with a 2-His-l-carboxylate facial triad. Dioxygen is labelled to indicate the fate of each oxygen atom. Adapted from Koehntop, Emerson, Que, 2005.) 

The Rieske dioxygenases (so-called because they contain a Rieske [2Fe—2S] cluster in addition to the mononuclear iron centre) catalyse cw-dihydroxylation of arene double bonds using NADH as the source of two electrons again, both dioxygen atoms are incorporated into the cA-diol product. 

The fourth class, the pterin-dependent hydroxylases, includes the aromatic amino acid hydroxylases, which use tetrahydrobiopterin as cofactor for the hydroxylation of Phe, Tyr, and Trp. The latter two hydroxylases catalyse the rate-limiting steps in the biosynthesis of the neurotransmitters/hormones dopamine/noradreanalme/ adrenaline and serotonin, respectively. 

This of course goes a long way to explaining the association of scurvy with vitamin C dehciency, and the successful utilisation by the British navy of lime juice as a means of prevention of the disease — hence the expression limey for British sailors. 

Interestingly, cysteine dioxygenase, among a growing number of other iron(ll) oxygenases, has the carboxylate residue replaced by another histidine. 

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The choice of iron chelators on the basis of both molecular and cellular criteria was discussed in 2003 (374). One 2005 review is concerned with the design of orally active iron chelators (375), another considers the prospects for effective clinical use of several hydro-x5rpyridinones, dealing with novel species such as the 1-allyl compound as well as with the established deferiprone (LI) and desferrioxamine (Desferal, DFO) (376). A review dated 2006 deals with relevance of iron mobilization from both transferrin and other iron-containing proteins by LI to the treatment of various anemias and other iron-overload conditions (377). Two 2007 reviews concentrate on LI, as the only hydroxypyridinone in general clinical use. One author concludes that, on balance, LI is to be preferred to DFO. This conclusion is on the grounds that, despite the not infrequent occurrence of minor side effects, the incidence of serious side effects... 

Other Iron-Containing Proteins Dinuclear Nonhaem Iron Enzymes... 

Spectroscopic data obtained from spectroelectrochemical experiments require careful and case-specific analysis. The Fe /Fe redox couple has a unique role in diflferent iron-containing proteins. It is hypothesised that the mammalian iron-transport protein transferrin uses the Fe /Fe redox couple as a switch that controls the time and site-specific release of iron, while other iron-containing proteins, such as myoglobin, are able to hold on to iron in both oxidation states. Therefore, it is very important to evaluate the protein and its interaction with both the oxidised and reduced states of iron and accordingly develop a data-analysis model. The spectroelectrochemical response of an iron binding protein can be ideal Nernstian, non-Nernstian resulting from coupled... 

Although iron deficiency anemia is characterized by decreased levels of hemoglobin and other iron-containing proteins in the blood, the iron-containing cytochromes and Fe-S centers of the electron transport chain in tissues such as skeletal muscle are affected as rapidly. Fatigue in iron deficiency anemia, in patients such as Ann O Rexia (see Chapter 16), results, in part, from the lack of electron transport for ATP production. 

Chapter 6). Other iron-sulfur proteins, so named because they contain iron sulfur clusters of various sizes, include the rubredoxins and ferredoxins. Rubredoxins are found in anaerobic bacteria and contain iron ligated to four cysteine sulfurs. Ferredoxins are found in plant chloroplasts and mammalian tissue and contain spin-coupled [2Fe-2S] clusters. Cytochromes comprise several large classes of electron transfer metalloproteins widespread in nature. At least four cytochromes are involved in the mitrochondrial electron transfer chain, which reduces oxygen to water according to equation 1.29. Further discussion of these proteins can be found in Chapters 6 and 7 of reference 13. 

Peroxidases are heme iron-containing proteins similar in structure to that of cytochromes P450. The major difference is that peroxidases have histidine as the axial ligand instead of cysteine, and there are also other polar amino acids close to the heme iron that help to catalyze the peroxidase function of the enzyme (41). The result is that the peroxidases very rapidly catalyze the reduction of hydroperoxides to alcohols (or water in the case of... 

There are many other proteins that contain iron in a form that is neither in haem nor in iron-sulfur clusters. We have already encountered the iron storage and transport proteins, ferritin and transferrin (see Chapter 8). We propose to discuss here two other classes of iron-containing proteins, those with mononuclear non-haem iron centres and those with dinuclear non-haem iron centres. 

Iron is essential for life and is required for many different types of iron-containing proteins. Microbes and other organisms go to extraordinary lengths to acquire Fe. Many microbes secrete specific and high affinity Fe chelators known as siderophores. More than 200 are known in bacteria alone (Neilands 1981). Siderophores overcome the problem of the low solubility of Felll especially in oxidising environments, and... 

Copper in proteins is not usually accompanied by any other cofactors such as hemes or inorganic sulfur in iron-containing proteins, so that the... 

A large number of iron-containing proteins form nitrosyl complexes. Heme proteins, iron-sulfur proteins, and other iron proteins such as nonheme iron dioxygenases all form characteristic nitrosyl complexes. In enzymes in which the metal center has an open coordination position, NO often can be bound without severe disruption of the site. This introduces the possibility of reversibility of inhibition. 

The abundance of iron as a transition metal in proteins is enormous and the diversity of functions performed by iron containing proteins is large. In terms of classification we follow the scheme of our previous reviews in forming two major groups, heme iron proteins and non-heme iron proteins. The latter class is divided into two sub-groups. One comprises iron-sulfur proteins and the other consists of those non-heme iron proteins which are not iron-sulfur proteins i.e. involve coordination with nitrogen and/or oxygen. We commence with the latter. 

In addition to NAD and flavoproteins, three other types of electron-carrying molecules function in the respiratory chain a hydrophobic quinone (ubiquinone) and two different types of iron-containing proteins (cytochromes and iron-sulfur proteins). Ubiquinone (also called coenzyme Q, or simply Q) is a lipid-soluble ben-zoquinone with a long isoprenoid side chain (Fig. 19-2). The closely related compounds plastoquinone (of plant chloroplasts) and menaquinone (of bacteria) play roles analogous to that of ubiquinone, carrying electrons in membrane-associated electron-transfer chains. Ubiquinone can accept one electron to become the semi-quinone radical ( QH) or two electrons to form ubiquinol (QH2) (Fig. 19-2) and, like flavoprotein carriers, it can act at the junction between a two-electron donor and a one-electron acceptor. Because ubiquinone is both small and hydrophobic, it is freely diffusible within the lipid bilayer of the inner mitochondrial membrane and can shuttle reducing equivalents between other, less mobile electron carriers in the membrane. And because it carries both electrons and protons, it plays a central role in coupling electron flow to proton movement. 

The second class of iron-containing proteins which have been well-studied by Mossbauer spectroscopy, and by other resonance techniques, are the iron-sulfur proteins. These molecules are also known by the name, ferredoxins. Iron-sulfur proteins in several varieties serve as electron-transport agents for processes in plants, bacteria, and mammals. Perhaps the most-studied physiological process involving the iron-sulfur proteins is the study of their role in photosynthesis. This subject has been extensively reviewed by Arnon 126,135), Hind and Olson 127), Hall and... 

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