Nomenclature of Electron-Transfer Proteins
Contents of this section
6.1 Type 1 Copper Proteins
The Cu(II) state of this category has an intense blue color due to a thiolate ligand to Cu(II) charge transfer, and unusual EPR properties arising from the asymmetrical Cu site (distorted trigonal-pyramidal). The proteins all have a low molecular mass and have, so far, rather arbitrarily been divided into sub-groups, such as azurins, plastocyanins, pseudoazurins, amicyanins and various other blue proteins. Of these the azurins, amicyanins, pseudo-azurins and plastocyanins apparently have similar copper coordination by two histidine, one cysteine and one methionine residue. Where the function of Type I copper proteins is known, it is invariably electron transfer. As yet the names for these proteins are all trivial and are often derived from source, function or color. The different classes are usually discerned on the basis of their primary and tertiary structure.
The first bacterial blue proteins to be described were called azurins. Rusticyanin is another example of a bacterial protein. It has unusual properties with a reduction potential of 680 mV, and is functional at pH 2. The azurins have well-defined electron-transfer functions.
The so-called pseudo-azurins differ from the azurins in the N-terminal amino acid sequence and the optical spectra, which resemble those of plastocyanins.
The blue proteins known as plastocyanins occur in plants, blue-green and green algae. Their electron transfer role is well defined, i.e. from the bc1 complex (EC 22.214.171.124) to the photooxidized P-700.
Amicyanins are electron carriers between methylamine dehydrogenase and cytochrome c, with a characteristic amino acid sequence.
Of the remaining blue proteins stellacyanin is a well-known example. Umecyanin, plantacyanin and mavicyanin are also considered to belong to this group. Although these proteins undergo redox reactions in vitro, their true biological function remains unknown. Most of these proteins exhibit an unusual EPR signal in which the copper hyperfine splitting pattern is poorly resolved. There is good evidence that at least for stellacyanin, methionine does not function as a ligand for copper.
6.2 Type 2 Copper Proteins
The copper centres in these proteins are spectroscopically consistent with square planar or pyramidal coordination, containing oxygen and/or nitrogen ligation. The Cu(II) is EPR active, with a 'normal' signal. There is no intense blue color. This group includes the copper/zinc superoxide dismutase (EC 126.96.36.199), dopamine b-monooxygenase (EC 188.8.131.52), galactose oxidase (EC 184.108.40.206) and the various copper-containing amine oxidases. Some members of this last group may also contain an organic prosthetic group, such as PQQ (see section 10), or a modified amino-acid residue.
6.3 Type 3 Copper Proteins
In this group a pair of copper atoms comprise a dinuclear centre, with no EPR activity as for single Cu's. The best known example of an enzyme containing a single Type 3 centre is tyrosinase (catechol oxidase, EC 220.127.116.11). This protein contains a metal centre which is a structural analogue of the dinuclear copper centre in hemocyanin (ref 31).
6.4 Multi-Copper Oxidases
In addition to the above, there are several proteins with catalytic activity that contain Types 1, 2 and 3 centres in various stoichiometric ratios. These include L-ascorbate oxidase (EC 18.104.22.168), laccase (EC 22.214.171.124) and ceruloplasmin (ferro-oxidase, EC 126.96.36.199), the latter two having aromatic diamine and diphenol oxidase activity. There is growing evidence that in these proteins the Type 2 and Type 3 copper centres are juxtaposed. Recently it has been shown that in L-ascorbate oxidase, a trinuclear copper site is present, consisting of a type 3 copper site, very close (3.9 Å) and possibly bridged to a type 2 copper site (ref 32). There is a view that ceruloplasmin functions as a ferro-oxidase and the Fe(III) produced in this reaction can then oxidize the same substrates as laccase.
6.5 Copper Centres in Cytochrome Oxidase
There are two copper centres that appear to be unique. Both are present in cytochrome-c oxidase (EC 188.8.131.52). The first appears to be an isolated metal ion and has been referred to as Cud and CuA. The second appears to be part of a dinuclear centre with cytochrome a3. It has been referred to as Cuu, Cua3 and CuB. At the moment the ascriptions CuA and CuB are most frequently used; however, the recent discovery (ref 33) of a cytochrome oxidase in which cytochrome a has been replaced by cytochrome b, leads to the recommendation that CuB shall be referred to as Cua3.
There is a striking similarity between two of the Cu centres of N2O reductase and CuA (ref 34, 35).
7. Molybdenum Proteins (see Note)
Note An expert panel is advising NC-IUB on the listing of these enzymes.7.1 Molybdenum enzymes (general)
Molybdenum enzymes contain molybdenum at the catalytic center responsible for reaction with substrate. They may be divided into those that contain the iron-molybdenum cofactor and those that contain the pterin-molybdenum cofactor.
7.2 Additional centres
If a molybdenum enzyme contains flavin, it may be called either a molybdenum flavoprotein or a flavomolybdenum protein, as indicated above. Other centres should be treated similarly, e.g. an iron-sulfur molybdenum protein.
7.3 Molybdenum enzymes containing the iron-molybdenum cofactor
The only enzymes at present known to belong to this group are the nitrogenases (EC 184.108.40.206; and EC 220.127.116.11): see pp 89-116 in (ref 36) and pp 91-100 in (ref 37).
7.4 Molybdenum enzymes containing the pterin-molybdenum cofactor
These enzymes [see pp 411-415 in (ref 36) and (ref 38)] may be divided into those in which the molybdenum bears a cyanide-labile sulfido (or thio - see Note 1) ligand i.e. containing the S2- ligand as Mo=S) and those lacking this ligand. The former group includes xanthine oxidase (EC 18.104.22.168), xanthine dehydrogenase (EC 22.214.171.124), aldehyde oxidase (EC 126.96.36.199) and purine hydroxylase (EC: see Note 2 and 3). These may be called 'molybdenum-containing hydroxylase' as is widely done. Molybdenum enzymes lacking the sulfide (thio) ligand include sulfite oxidase (EC 188.8.131.52), NAD(P)+-independent aldehyde dehydrogenase and nitrate reductases (assimilatory and dissimilatory) (EC 184.108.40.206-3).
Note 1 Inorganic chemists also use 'thio' for the S2-ligand, especially when this ligand is bound to one metal only, forming a M=S unit. The fully systematic name 'sulfido' is to be preferred, since this applies to both the M=S unit and the bridging S2- ligand.7.5 Other molybdenum enzymes
Note 2 Not yet listed in Enzyme Nomenclature (ref 1).
Note 3 An expert panel is advising NC-IUB on the listing of these enzymes.
Molybdenum enzymes not yet sufficiently characterized for them to be assigned to classes include formate dehydrogenase (EC 220.127.116.11), carbon-monoxide oxidase (EC 18.104.22.168), tetrathionate reductase (EC 22.214.171.124), chlorate reductase (EC 126.96.36.199), trimethylamine-N-oxide reductase (EC 188.8.131.52) and biotin-S-oxide reductase.
8. Nickel Proteins
Nickel has now been shown to be an integral component of a number of redox enzymes. Many but not all hydrogenases contain nickel in addition to iron-sulfur clusters, and it appears that it is a common constituent of those hydrogenases whose function is to oxidize rather than to evolve hydrogen. The nickel centre can undergo facile changes in oxidation number. Evidence has been presented that hydrogen, as well as the competitive inhibitor carbon monoxide, can bind directly to nickel (ref 39, 40), implying that the nickel centre might be the active site of these enzymes.
A nickel-tetrapyrrole coenzyme, Co-F430, is present in the methyl CoM reductase and in methanogenic bacteria; the tetrapyrrole is classed as a tetrahydrocorphinoid, being intermediate in structure between porphyrin and corrin. Changes in redox state, as well as changes in nickel coordination, have recently been observed with enzymes of bacteria (ref 41).
The nickel-containing carbon monoxide dehydrogenase (EC 184.108.40.206) is now recognized to be a CO-dependent acetyl-CoA synthase. Little is known about the structure of the nickel site but there is some evidence that it is a component of an iron-sulfur cluster.
9. Vanadium Proteins
Vanadium has a role in a number of biological systems. Bromoperoxidases from marine algae contain vanadium as a prosthetic group essential for enzymic activity (ref 42). These enzymes appear to be involved in the formation of organo-halo species secreted by seaweeds. The vanadium ion is present in these enzymes in the 5+ oxidation state (in the resting state); data have not yet been provided that the vanadium undergoes redox changes during catalysis. The vanadium ion seems to serve as the binding site for hydrogen peroxide and bromide.
Evidence (ref 43) has been presented that in bacteria two nitrogen fixing systems are present: the conventional molybdenum nitrogenase and an alternative nitrogen-reducing enzyme complex. The alternative nitrogenase complexes were shown to contain a vanadium-iron cofactor, analogous to the MoFe cofactor in the conventional enzymes. These VFe nitrogenases differ from the conventional nitrogenases in substrate specificity.
Quinoproteins contain pyrroloquinoline quinone (PQQ; also called methoxatin), or an amino-acid-derived quinone as a cofactor. PQQ, which has been shown to be present in some bacterial dehydrogenases, is non-covalently bound. Other quinoproteins contain an amino-acid residue in their protein chain which is modified to a quinone prosthetic group. Some quinoproteins also contain a redox-active metal ion, and as such some of them may already have been mentioned in previous sections. Two subgroups have already been classified:
(a) Dehydrogenases. Many gram-negative bacteria contain quino-protein dehydrogenases (ref 44), such as methanol dehydrogenase (EC 220.127.116.11) which occurs in all gram-negative methanol utilizers investigated so far. Two different types of quinoprotein alcohol dehydrogenases occur in alkane or alcohol-grown Pseudomonas species. Glucose dehydrogenase also occurs in two quite different types, the soluble (EC 18.104.22.168) and the membrane-bound ones. Amine dehydrogenase (EC 22.214.171.124) is the first quinoprotein for which the 3-dimensional structure has been elucidated by X-ray diffraction (ref 45). Its cofactor contains a tryptophan dimer (ref 46) with one indole ring oxidized to the o-quinone group.
(b) Oxidases. The only bacterial quinoprotein oxidase known is methylamine oxidase (ref 47). Mammalian examples are pig kidney diamine oxidase and bovine serum amine oxidase (both EC 126.96.36.199). All these oxidases contain also copper as a second redox centre and they all form hydrogen peroxide as a product. The organic prosthetic group is one of the tyrosine residues in the protein chain, which is modified to topaquinone (or to 6-hydroxydopaquinone) (ref 48).
When the presence of such a quinone has been established, it is recommended that the name of the protein be prefixed with: 'quinone-containing'.
11. Metal-Substituted Metalloproteins
Scientists from several areas, dealing with spectroscopy and electron-transfer mechanisms, often use metalloproteins in which a metal at the active site has been substituted by another metal ion, like Co, Zn, Hg, Cd. Examples are zinc-substituted cytochromes and cobalt-substituted ferredoxins.
The names for such modified proteins are easily given by using indications like: 'zinc-substituted ....'. In case of multi-metal proteins, where ambiguity might arise about which metal has been substituted, one could easily add in parentheses the name of the metal that has been replaced, such as: cobalt- substituted [Fe] nitrogenase.
In formulae fragments or short names one could use the following notation: [3Fe1Co-4S]2+, cytochrome c'[FeCoFe], plastocyanin[CuHg]. When needed the particular isotope of the new metal can be also mentioned, as in plastocyanin[Cu113Cd]
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