Nomenclature of Electron-Transfer Proteins
The processes of oxidation in living cells are catalysed by the cooperation of a number of enzyme and coenzymes that transfer reducing equivalents, either hydrogen atoms or electrons, in successive steps from an initial donor to a final acceptor. The enzymes concerned can be named according to the general principles laid down in Enzyme Nomenclature (ref 1).
At the end of the 1984 edition a survey, written in 1978, about electron transfer proteins is given. Since that time not only have many new electron transfer proteins been reported, but also practices in many subfields have changed, so that an update and extension of these rules is timely.
Electron transfers are e.g. the oxidation of intermediary metabolites by molecular oxygen in the mitochondria of animal, plant and protist cells, and in the protoplasmic membranes of those protists that lack mitochondria; these often require the successive transfer of hydrogen atoms or electrons, first to NAD+, then from NADH to an ubiquinone (Q), next from QH2 to ferricytochrome c and finally from ferrocytochrome c to oxygen. These reactions are catalysed, e.g., by an oxidoreductase using NAD+ or NADP+ as acceptor, NADH:Q oxidoreductase (EC 188.8.131.52) (see note 1) QH2:cytochrome-c oxidoreductase (EC 184.108.40.206), and ferrocytochrome-c:O2 oxidoreductase (EC 220.127.116.11), respectively. In some instances, NADP+ is used as the first hydrogen acceptor and an additional enzyme, NAD(P)+ transhydrogenase (EC 18.104.22.168-2), is required for the initial reduction of NAD+. In other cases, particularly with substrates of higher redox potential, neither NAD+ nor NADP+ is required and appropriate enzymes catalyse either the direct reduction of Q (for example, succinate dehydrogenase, EC 22.214.171.124) or introduce electrons into the sequence via the so-called electron-transfer flavoprotein (see below). Similarly, in the light-driven oxidation of water that occurs in the chloroplasts of green plants, hydrogen atoms or electrons are transferred successively to plastoquinone (PQ), thence to plastocyanin and finally to NADP+ in reactions catalysed by photosystem II, PQH2:plastocyanin oxidoreductase (EC: see note 2), photosystem I (EC: see Note 2), and ferredoxin:NADP+ reductase (EC 126.96.36.199), respectively. Although the photosystems II and I are not usually classified as enzymes, they could be designated H2O:PQ oxidoreductase (light-driven) and plastocyanin:ferredoxin oxidoreductase (light-driven), respectively.
Note 1 Also called NADH dehydrogenase (ubiquinone), formerly given the systematic name NADH:(acceptor) oxidoreductase.Often the metal-containing electron transport proteins are closely associated with, or a part of, an enzyme and in these cases the EC numbers - as far as is unambiguously known - are also listed. Many of these enzymes are in fact large protein complexes and consist of a number of subunits; some of these subunits are electron carriers that were discovered before it was recognized that they are indeed subunits of their respective enzymes. For example, ubiquinol-cytochrome-c reductase (EC 188.8.131.52) contains a diheme cytochrome b (previously considered to be separate cytochromes, i.e. b-562 and b-566, respectively), cytochrome c1 and an iron-sulfur cluster. These electron carriers catalyse electron transfers within the enzyme, and participate in overall reaction mechanisms which may be quite complex and are still subject to clarification. Although each of these electron-transfer carriers, being a catalytically active protein, satisfies the all-embracing definition of an enzyme, for example, cytochrome c1 in QH2:ferricytochrome c oxidoreductase, it is undesir-able to give the subunit of an enzyme a separate enzyme name. Moreover, since much is known about the electron-carrying centres of these enzymes, it is more appropriate to classify them on the basis of the chemical structure of the prosthetic group and the manner of their attachment to the protein. Finally, many redox enzymes occur for which the electron transfer function of the protein has not yet been proven, such as in the vanadium proteins; these have nevertheless been included in the present document.
Note 2 Not yet listed in Enzyme Nomenclature (ref 1).
Several groups of electron-transfer proteins are classified below: flavoproteins, proteins containing reducible disulfide groups, cytochromes, iron proteins, copper proteins, molybdenum proteins, nickel proteins, vanadium proteins and quinoproteins.
When the electron transfer protein contains more than one redox-active prosthetic group, this should be indicated as follows: the group reacting with the physiological electron donor should be listed first and the group reacting with the physiological electron acceptor should be listed last. Thus, yeast L-lactate dehydrogenase (cytochrome) (EC 184.108.40.206) would be indicated as a flavohemoprotein. If additional groups are present they should be indicated as illustrated for xanthine oxidase (EC 220.127.116.11): molybdenum-(2[2Fe-2S])-flavoprotein. If the physiological electron donor and acceptor are not known, then all the prosthetic groups should be enclosed in parentheses.
In many cases rather recent examples from the literature have been included, although this might have some disadvantages (see note).
Note It has to be realized that many systematic names for proteins quite often have to be adjusted because they - later - appear to have a different or additional function.Finally, spectroscopists often use metal proteins in which the natural metal has been replaced by another metal ion (e.g. Fe replaced by Co or Zn). These proteins are briefly discussed in section 11.
Flavoproteins commonly contain one of two prosthetic groups, FMN (e.g. NADH dehydrogenase, EC 1.6.99.l) and FAD. The FMN is non-covalently bound in all known cases. FAD may be non-covalently bound (e.g. in dihydrolipoamide dehydrogenase (NADH), EC 18.104.22.168) or covalently bound by a methylene bridge between the benzene ring of the benzo[g]pteridine-2,4-dione and an amino acid residue, such as cysteine, histidine or tyrosine, in the protein (e.g. succinate dehydrogenase, EC 22.214.171.124), or directly at ring position 6. 8-Hydroxy-pyrimidino[4,5-b]quinoline-2,4-dione functions as prosthetic group in methanogens and in deoxyribodipyrimidine photolyase (EC 126.96.36.199).
Apart from a few exceptions where the role of the flavin is not clear, e.g. tartronate-semialdehyde synthase (EC 188.8.131.52), flavoproteins carry out oxidation-reduction reactions, in which one substrate is oxidized and a second is reduced. For all these enzymes each catalytic cycle consists of two distinct processes, the acceptance of redox equivalents from a reducing substrate and the transfer of these equivalents to an oxidized acceptor. Accordingly, the catalysed reactions consist of two separate half-reactions: a reductive half-reaction in which the flavin is reduced and an oxidative half-reaction, in which the reduced flavin is reoxidized.
The nature of the substrate involved in the two separate half-reactions has been used as the basis for a scheme in which five broad classes of flavoenzymes are defined (ref 2):
(a) Transhydrogenase, where two-electron equivalents are transferred, along with the appropriate hydrogen ions, from one organic substrate to another.
(b) Dehydrogenase-oxidase, where two-electron equivalents are transferred to the flavin from an organic substrate, where molecular oxygen is the oxidizing substrate, being reduced to H2O2.
(c) Dehydrogenase-monooxygenase, where the flavin is reduced, generally by a reduced pyridine nucleotide, and where on oxidation with O2 in the presence of a co-substrate one atom of oxygen is inserted into the co-substrate, while the other is reduced to H2O.
(d) Dehydrogenase-electron transferase, where the flavin is reduced by 2-electron transfer from a reduced substrate and then reoxidized in sequential single electron transfers to acceptors, such as cytochromes and iron-sulfur proteins. An example is the NADPH cytochrome-b5 reductase (EC 184.108.40.206). This class might be further subdivided to distinguish those enzymes which are functioning in the reverse sense, i.e., those which receive electrons one at a time and then transmit them in a two-electron step in the reduction of a pyridine nucleotide. An example is ferredoxin NADP+ reductase (EC 220.127.116.11).
(e) Electron transferase, where the flavin is reduced and reoxidized in 1-electron steps. There are two examples. The first is the so-called electron-transfer flavoprotein that catalyses the transfer of electrons from another enzyme, namely butyryl-CoA dehydrogenase (EC 18.104.22.168), acyl-CoA dehydrogenase (EC 22.214.171.124), sarcosine dehydrogenase (EC 126.96.36.199) or dimethylglycine dehydrogenase (EC 188.8.131.52), to the respiratory chain. The second is flavodoxin, a group of flavoproteins of low potential that catalyse electron transfer between two other redox proteins as part of photosynthetic, nitrogen- or sulfate-reducing or hydrogen-evolving systems.
It should be noted that flavoproteins can act in sequence. The most extreme case is found in the pathway for the b-oxidation of fatty acids. A flavoprotein dehydrogenase first oxidizes the saturated fatty acyl CoA. The dehydrogenase then transfers its electron via a second flavoprotein, the electron-transferring flavoprotein, to the membrane-bound iron-sulfur flavoprotein, electron-transferring protein ubiquinone oxidoreductase. This last protein reduces coenzyme Q, thus delivering electrons to the respiratory chain. Similar sequences of reactions are found in the catabolic pathways of several amino acids and in the operation of the mitochondrial one-carbon cycle.
3. Proteins Containing Reducible Disulfide
Lipoylproteins containing lipoic acid covalently bound by an amide link between its carboxyl group and the 6-amino group of a lysine residue in the protein are involved in the oxidation of both pyruvate and 2-oxoglutarate. The disulfide group of the lipoic acid is both reduced and acylated by pyruvate dehydrogenase (lipoamide) (EC 184.108.40.206) and oxoglutarate dehydrogenase (lipoamide) (EC 220.127.116.11). Thus, lipoylproteins act as both hydrogen and acyl acceptors. They are sub-units of the pyruvate and 2-oxoglutarate dehydrogenase complexes.
The flavoproteins catalysing the reduction of lipoamide, oxidized glutathione, thioredoxin, and glutaredoxin by reduced nicotinamide-adenine nucleotides (EC 18.104.22.168, 22.214.171.124 and 126.96.36.199, respectively) contain reducible cystine residues that are involved in the electron-transfer reaction; NADPH-mercury(II) reductase (EC 188.8.131.52) also contains a reducible cystine. Thioredoxin, which is required for the reduction of cytidine diphosphate to deoxycytidine diphosphate, is itself an electron-transferring protein with a cystine residue as the electron-transferring centre; glutaredoxin is similar. Thioredoxins of higher plants are involved in the regulation of enzymes in the Calvin cycle; they are reduced by ferredoxin, not NAD(P)H, but the enzyme(s) have not been characterized.
References for this section
1. International Union of Biochemistry (1984). Enzyme Nomenclature, Recommendations 1984, Academic Press, Orlando, Florida, U.S.A.
2. Hemmerich, P., Massey, V. & Fenner, H. (1972) FEBS Lett. 84, 5-21.