UPDATE ONRGeEvNieEwCOMPLETIONS AND ANNOTATIONS Vasiliou, Ross and Nebert Table 2. Human CYB5R genes listed in the HUGO gene nomenclature committee database. Approved gene symbol CYB5R1 CYB5R2 CYB5R3 CYB5R4 Approved gene name Cytochrome b5 reductase-1 Cytochrome b5 reductase-2 Cytochrome b5 reductase-3 Cytochrome b5 reductase-4 Location 1q32.1 11p15.4 22q13.31- qter 6pter- q22.33 Sequence accession IDs AF169481 NM_016243 AF169802 NM_016229 M16461 AF169803 NM_016230 Aliases humb5R2, 1500005G05Rik Previous symbols NQO3A2 DIA1 NCB5OR b5+b5R, dJ676J13.1 there are many enzymes that can be characterised as ‘diaphorases’. The term ‘DT’-diaphorase was originally used by Ernster, to describe what is now known as NQO1, because the enzyme worked with equal facility, employing either DPNH (NADH) or TPNH (NADPH). Edwards et al.29 discuss a series of ‘diaphorases’ deﬁned in human tissues. Diaphorase-1 was NADH cytochrome b5 reductase-3 (Table 2).30,31 Diaphorase-2 was the major enzyme in erythrocytes catalysing the oxidation of NADPH. Diaphorase-3 was the principal source of oxidised coenzyme in sperm. Diaphorase-4 was characterised by Edwards et al.,29 and this enzyme was found to be identical to the previously characterised DT-diaphorase.32 Interestingly, Edwards and colleagues also showed that diaphorase-4 activity was absent in approximately 4 per cent of the UK population, which is in agreement with more recent genetic studies of the prevalence of the NQO1*2 allele.14. All diaphorases discussed by Edwards29 are distinct gene products but, because of their similarity based on enzymic function rather than evolutionary divergence, searches for ‘NQO1’ in some databases will still return descriptions of ‘cytochrome b5 reductase’. These cytochrome b5 reductase ‘diaphorases’ are not evolutionarily related, are very different functionally and are encoded by separate gene loci (Table 2). A second source of confusion involves the use of the generic term ‘quinone reductase’, because a wide variety of enzymes in prokaryotes, plants and animals can reduce quinones via both one- and two-electron steps. A search of the HUGO Gene Nomenclature Committee database using ‘NQO’ provided three hits—two NQO genes plus ‘NQO3A2’ (which actually encodes cytochrome b5 reductase-1)—the latter appears in the database because of its previous name as a diaphorase (see above). In fact, one of its aliases is ‘NQO3A2’, which has been listed in the http:// SNPper.chip.org/ database; the authors have pointed out this error to this organisation. A search of the SwissProt and TrEMBL databases using ‘NQO’ provided 168 hits (39 in SwissProt and 129 in TrEMBL), but not all of them belong to the ﬂavodoxin-2 family. The term ‘NQO’ has therefore been used for other enzymes and care should be taken to avoid such confusion. Figure 2. Phylogenetic organisation of selected NQO genes in bacteria and eukaryotes. Metma, Methanosarcina mazei (an archaebacter- ium); Cavpo, Cavia porcellus (guinea pig); Musmu, Mus musculus; Ratno, Rattus norvegicus; Bosta, Bos taurus; Canfa, Canis familiaris; Macfa, Macaca fascicularis (macaque); Ponpy, Pongo pygmaeus (orangutan); Homsa, Homo sapiens; Pantr, Pan troglodytes (chimpanzee); Xentr, Xenopus tropicalis; Danre, Danio rerio (zebraﬁsh); Oryla, Oryzias latipes (ray-ﬁnned ﬁsh); Galga, Gallus gallus (chicken); Tetni, Tetraodon nigroviridis (puffer ﬁsh); Pseae, Pseudomonas aeruginosa; Psepu, Pseudomonas putida; Rossp, Roseovarius_sp_217; Rhopa, Rhodopseudomonas palustri; BurcePC184, Burkholderia cenocepacia PC184; BurceAU1054, Burkholderia Burkholderia cenocepacia AU 1054; Frasp, Frankia sp; Cangl, Candida glabrata; Trimo, Triticum monococcum; Orysa, Oryza sativa (rice); Trive, Triphysaria versicolor; Arath, Arabidopsis thaliana; QR2, quinone reductase-2, which belongs to the ﬂavodoxin-1 fold, and not to the ﬂavodoxin-2 (NQO) fold. No NQO genes were found in Caenorhabditis elegans, Drosophila melanogaster or Ciona savignyi (sea squirt), nor in several plants whose genomic databases were searched. 332 q HENRY STEWART PUBLICATIONS 1473-9542. HUMAN GENOMICS. VOL 2. NO 5. 329–335 MARCH 2006