| Literature References | 1. HYDE, G.E., CRAWFORD, N.M. AND CAMPBELL, W.H.
The sequence of squash NADH:nitrate reductase and its relationship to the
sequences of other flavoprotein oxidoreductases. A family of flavoprotein
pyridine nucleotide cytochrome reductases.
J.BIOL.CHEM. 266 23542-23547 (1991).
2. KARPLUS, P.A. AND BRUNS, C.M.
Structure-function relations for ferredoxin reductase.
J.BIOENERG.BIOMEMBR. 26 89-99 (1994).
3. CAMPBELL, W.H. AND KINGHORN, J.R.
Functional domains of assimilatory nitrate and nitrite reductases.
TRENDS BIOCHEM.SCI. 15 315-319 (1990).
4. TAMURA, M., YUBISUI, T., TAKESHITA, M., KAWABATA, S., MIYATA, T. AND
IWANAGA, S.
Structural comparison of bovine erythrocyte, brain, and liver
NADH-cytochrome b5 reductase by HPLC mapping.
J.BIOCHEM.(TOKYO) 101 1147-1159 (1987).
5. OZOLS, J., CARR, S.A. AND STRITTMATTER, P.
Identification of the NH2-terminal blocking group of NADH-cytochrome b5
reductase as myristic acid and the complete amino acid sequence of the
membrane-binding domain.
J.BIOL.CHEM. 259 13349-13354 (1984).
6. YUBISUI, T., MURAKAMI, K., SHIRABE, K., TAKESHITA, M., ZENNO, S.,
TOMATSU, S. AND FUKUMAKI, Y.
Structural analysis of NADH-cytochrome b5 reductase in relation to
hereditary methemoglobinemia.
PROG.CLIN.BIOL.RES. 319 107-119 (1989).
7. LU, G., CAMPBELL, W.H., SCHNEIDER, G. AND LINDQVIST, Y.
Crystal structure of the FAD-containing fragment of corn nitrate reductase
at 2.5 A resolution: relationship to other flavoprotein reductases.
STRUCTURE 2 809-821 (1994).
8. NISHIDA, H., INAKA, K., YAMANAKA, M., KAIDA, S., KOBAYASHI, K. AND
MIKI, K.
Crystal structure of NADH-cytochrome b5 reductase from pig liver at 2.4A
resolution.
BIOCHEMISTRY 34 2763-2767 (1995).
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| Documentation | Flavoprotein pyridine nucleotide cytochrome reductases [1] (FPNCR) catalyse
the interchange of reducing equivalents between one-electron carriers and
the two-electron-carrying nicotinamide dinucleotides. The enzymes include
ferredoxin:NADP+ reductases (FNR) [2]; plant and fungal NAD(P)H:nitrate
reductases [1,3]; NADH:cytochrome b5 reductases [4]; NADPH:P450 reductases;
NADPH:sulphite reductases; nitric oxide synthases; phthalate dioxygenase
reductase; and various other flavoproteins.
NADH:cytochrome b5 reductase (CBR) serves as electron donor for cytochrome
b5, a ubiquitous electron carrier (see signature CYTOCHROMEB5), thus
participating in a variety of metabolic pathways (including steroid
biosynthesis, desaturation and elongation of fatty acids, P450-dependent
reactions, methaemoglobin reduction, etc.). A membrane-bound form of CBR is
located on the cytosolic side of the endoplasmic reticulum, while a soluble
form is found in erythrocytes [4]. In the membrane-bound form, the N-
terminal residue is myristoylated [5]. Deficiency of the erythrocyte form
causes hereditary methaemoglobinemia [6].
In biological nitrate assimilation, reduction of nitrate to nitrite is
catalysed by the multidomain redox enzyme NAD(P)H:nitrate reductase (NR).
Three forms of NR are known: an NADH-specific enzyme found in higher plants
and algae (EC 1.6.6.1); an NAD(P)H-bispecific enzyme found in higher plants,
algae and fungi (EC 1.6.6.2); and an NADPH-specific enzyme found only in
fungi (EC 1.6.6.3) [3]. NR can be divided into 3 structure/function domains:
the molybdopterin cofactor binds in the N-terminal domain; the central
region is the cytochrome b domain, which is similar to animal cytochrome b5
(see signature CYTOCHROMEB5); and the C-terminal portion of the protein is
occupied by the FAD/NAD(P)H binding domain, which is similar to CBR [3].
The catalytic reduction of nitrate to nitrite can be viewed as a single
polypeptide electron transport chain with electron flow from NAD(P)H ->
FAD -> cytochrome b5 -> molybdopterin -> NO(3). Thus, the flavin domain of
NR is functionally identical to CBR.
To date, the 3D-structures of the flavoprotein domain of corn nitrate
reductase [7] and of pig NADH:cytochrome b5 reductase [8] have been solved.
The overall fold is similar to that of ferredoxin:NADP+ reductase [2]:
the FAD-binding domain (N-terminal) has the topology of an anti-parallel
beta-barrel, while the NAD(P)-binding domain (C-terminal) has the topology
of a classical pyridine dinucleotide-binding fold (i.e., a central parallel
beta-sheet flanked by 2 helices on each side).
CYTB5RDTASE is a 6-element fingerprint that provides a signature for the
cytochrome b5 reductase family. The fingerprint was derived from an initial
alignment of 12 sequences - the motifs were drawn from short conserved
regions spanning virtually the full alignment length - motifs 1-3 lie
in the beta-barrel domain, and motifs 4-6 in the NAD(P)-binding domain.
Motif 2 is involved in binding the isoalloxazine ring of FAD (cf. motif 2
of FPNCR); motif 4 includes residues involved in binding the diphosphate
group of the pyridine nucleotide (cf. motif 4 of FPNCR); motif 5
corresponds to motif 6 of FPNCR; and motif 6 contains a conserved Cys
residue that may interact with NAD(P)H, and is necessary for efficient
electron transfer (cf. motif 8 of FPNCR). Two iterations on OWL26.2 were
required to reach convergence, at which point a true set comprising 47
sequences was identified. Several partial matches were also found: a
hypothetical yeast protein (S54059), identified as a putative CBR, matches
motifs 2-5; 2 hypothetical yeast proteins, similar to NR (YKP0_YEAST and
S49640), match motifs 2, 4, 5, 6 and 3-6, respectively; NIA_LOTTE is a
C-terminal fragment of NR matching motifs 4-6; FNR from Anabaena
(FENR_ANASO) matches motifs 3-5; 2 [2Fe-2S] ferredoxin/FNR fusion proteins
(MEMC_METCA and XYLZ_PSEPU) match motifs 3, 4 and 6; plant FNRs
(FENR_ORYSA, FENS_ORYSA, FENR_PEA, FENR_VICFA, FENR_MESCR and S53305),
bacterial [2Fe-2S] ferredoxin/FNR fusion proteins (C48360 and PPU040525),
and the reductase component of the phenoxybenzoate dioxygenase system
(S44172) match motifs 3 and 4; animal P450 reductases (NCPR_RAT, RATNCPR6,
NCPR_CAVPO, NCPR_HUMAN, NCPR_MOUSE, NCPR_PIG and NCPR_RABIT) match motifs
4 and 5; cytochrome-c3 hydrogenase (S48834) matches motifs 3 and 5; and
[2Fe-2S] ferredoxin/FNR fusion protein (PCCBDABC3) matches motifs 4 and 6.
An update on SPTR37_9f identified a true set of 48 sequences, and 23
partial matches.
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| Sequence Titles | NC5R_BOVIN NADH-CYTOCHROME B5 REDUCTASE (EC 1.6.2.2) - BOS TAURUS (BOVINE).
NC5R_HUMAN NADH-CYTOCHROME B5 REDUCTASE (EC 1.6.2.2) (B5R) - HOMO SAPIENS (HUMAN).
NC5R_RAT NADH-CYTOCHROME B5 REDUCTASE (EC 1.6.2.2) - RATTUS NORVEGICUS (RAT).
NC5R_YEAST PUTATIVE NADH-CYTOCHROME B5 REDUCTASE (EC 1.6.2.2) (P35) - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST).
NIA1_ARATH NITRATE REDUCTASE 1 (EC 1.6.6.1) (NR1) - ARABIDOPSIS THALIANA (MOUSE-EAR CRESS).
NIA1_BRANA NITRATE REDUCTASE, CLONE PBNBR1405 (EC 1.6.6.1) (NR) - BRASSICA NAPUS (RAPE).
NIA1_HORVU NITRATE REDUCTASE (EC 1.6.6.1) (NR) - HORDEUM VULGARE (BARLEY).
NIA1_ORYSA NITRATE REDUCTASE 1 (EC 1.6.6.1) (NR1) - ORYZA SATIVA (RICE).
NIA1_PHAVU NITRATE REDUCTASE 1 (EC 1.6.6.1) (NR-1) - PHASEOLUS VULGARIS (KIDNEY BEAN) (FRENCH BEAN).
NIA1_SOYBN INDUCIBLE NITRATE REDUCTASE 1 (EC 1.6.6.1) (NR) - GLYCINE MAX (SOYBEAN).
NIA1_TOBAC NITRATE REDUCTASE 1 (EC 1.6.6.1) (NR1) - NICOTIANA TABACUM (COMMON TOBACCO).
NIA2_ARATH NITRATE REDUCTASE 2 (EC 1.6.6.1) (NR2) - ARABIDOPSIS THALIANA (MOUSE-EAR CRESS).
NIA2_BRANA NITRATE REDUCTASE, CLONE PBNBR1412 (EC 1.6.6.1) (NR) - BRASSICA NAPUS (RAPE).
NIA2_PHAVU NITRATE REDUCTASE 2 (EC 1.6.6.1) (NR-2) - PHASEOLUS VULGARIS (KIDNEY BEAN) (FRENCH BEAN).
NIA2_SOYBN INDUCIBLE NITRATE REDUCTASE 2 (EC 1.6.6.1) (NR) - GLYCINE MAX (SOYBEAN).
NIA2_TOBAC NITRATE REDUCTASE 2 (EC 1.6.6.1) (NR2) - NICOTIANA TABACUM (COMMON TOBACCO).
NIA3_MAIZE NITRATE REDUCTASE 3 (EC 1.6.6.1) (NR) - ZEA MAYS (MAIZE).
NIA7_HORVU NITRATE REDUCTASE [NAD(P)H] (EC 1.6.6.2) - HORDEUM VULGARE (BARLEY).
NIA_ASPNG NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - ASPERGILLUS NIGER.
NIA_BEABA NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - BEAUVERIA BASSIANA (TRITIRACHIUM SHIOTAE).
NIA_BETVE NITRATE REDUCTASE [NAD(P)H] (EC 1.6.6.2) (NR) - BETULA VERRUCOSA (WHITE BIRCH) (BETULA PENDULA).
NIA_CICIN NITRATE REDUCTASE (EC 1.6.6.1) (NR) - CICHORIUM INTYBUS (CHICORY).
NIA_CUCMA NITRATE REDUCTASE (EC 1.6.6.1) (NR) - CUCURBITA MAXIMA (PUMPKIN) (WINTER SQUASH).
NIA_EMENI NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - EMERICELLA NIDULANS (ASPERGILLUS NIDULANS).
NIA_FUSOX NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - FUSARIUM OXYSPORUM.
NIA_LEPMC NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - LEPTOSPHAERIA MACULANS (BLACKLEG FUNGUS).
NIA_LOTJA NITRATE REDUCTASE (EC 1.6.6.1) (NR) - LOTUS JAPONICUS.
NIA_LYCES NITRATE REDUCTASE (EC 1.6.6.1) (NR) - LYCOPERSICON ESCULENTUM (TOMATO).
NIA_NEUCR NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - NEUROSPORA CRASSA.
NIA_PETHY NITRATE REDUCTASE (EC 1.6.6.1) (NR) - PETUNIA HYBRIDA (PETUNIA).
NIA_PHYIN NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - PHYTOPHTHORA INFESTANS (POTATO LATE BLIGHT FUNGUS).
NIA_PICAN NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - PICHIA ANGUSTA (YEAST) (HANSENULA POLYMORPHA).
NIA_SPIOL NITRATE REDUCTASE (EC 1.6.6.1) (NR) - SPINACIA OLERACEA (SPINACH).
NIA_USTMA NITRATE REDUCTASE [NADPH] (EC 1.6.6.3) (NR) - USTILAGO MAYDIS (SMUT FUNGUS).
NIA_VOLCA NITRATE REDUCTASE (EC 1.6.6.1) (NR) - VOLVOX CARTERI.
O00101 NITRATE REDUCTASE (NADPH) (EC 1.6.6.3) - PHAEOSPHAERIA NODORUM (SEPTORIA NODORUM).
O04926 NADH NITRATE REDUCTASE (EC 1.6.6.3) (NITRATE REDUCTASE (NADPH)) - SOLANUM TUBEROSUM (POTATO).
O13486 NITRATE REDUCTASE - METARHIZIUM ANISOPLIAE.
O16521 T05H4.5 PROTEIN - CAENORHABDITIS ELEGANS.
O16522 T05H4.4 PROTEIN - CAENORHABDITIS ELEGANS.
O24390 NADH NITRATE REDUCTASE (EC 1.6.6.3) - SOLANUM TUBEROSUM (POTATO).
O74557 PUTATIVE NADH-CYTOCHROME B5 REDUCTASE - SCHIZOSACCHAROMYCES POMBE (FISSION YEAST).
Q00303 NITRATE REDUCTASE - BOTRYTIS CINEREA (BOTRYOTINIA FUCKELIANA).
Q01696 NITRATE REDUCTASE - PENICILLIUM CHRYSOGENUM.
Q12561 NITRATE REDUCTASE (EC 1.7.99.4) - ASPERGILLUS ORYZAE.
Q42497 NITRATE REDUCTASE - CHLORELLA VULGARIS.
Q43042 NITRATE REDUCTASE APOENZYME (EC 1.6.6.1) (NITRATE REDUCTASE (NADH)) (ASSIMILATORY NITRATE REDUCTASE) - PETUNIA HYBRIDA (PETUNIA).
Q92237 NITRATE REDUCTASE - FUSARIUM MONILIFORME (GIBBERELLA FUJIKUROI).
Q00284 NITRATE REDUCTASE - ASPERGILLUS PARASITICUS.
YMI7_YEAST HYPOTHETICAL 35.8 KD PROTEIN IN RPM2-TUB1 INTERGENIC REGION - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST).
MCR1_YEAST NADH-CYTOCHROME B5 REDUCTASE PRECURSOR (EC 1.6.2.2) (P34/P32) - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST).
XYLZ_PSEPU TOLUATE 1,2-DIOXYGENASE ELECTRON TRANSFER COMPONENT [INCLUDES: FERREDOXIN; FERREDOXIN--NAD(+) REDUCTASE (EC 1.18.1.3)] - PSEUDOMONAS PUTIDA.
YMM5_YEAST HYPOTHETICAL 35.3 KD PROTEIN IN HMGS-TUB3 INTERGENIC REGION - SACCHAROMYCES CEREVISIAE (BAKER'S YEAST).
FENS_ORYSA FERREDOXIN--NADP REDUCTASE, ROOT ISOZYME PRECURSOR (EC 1.18.1.2) (FNR) - ORYZA SATIVA (RICE).
FENS_PEA FERREDOXIN--NADP REDUCTASE, ROOT ISOZYME PRECURSOR (EC 1.18.1.2) (FNR) - PISUM SATIVUM (GARDEN PEA).
FENS_TOBAC FERREDOXIN--NADP REDUCTASE, ROOT-TYPE ISOZYME PRECURSOR (EC 1.18.1.2) (FNR) - NICOTIANA TABACUM (COMMON TOBACCO).
FENT_ORYSA FERREDOXIN--NADP REDUCTASE, EMBRYO ISOZYME PRECURSOR (EC 1.18.1.2) (FNR) - ORYZA SATIVA (RICE).
MEMC_METCA METHANE MONOOXYGENASE COMPONENT C (EC 1.14.13.25) (METHANE HYDROXYLASE) - METHYLOCOCCUS CAPSULATUS.
O05933 2-OXO-1,2-DIHYDROQUINOLINE 8-MONOOXYGENASE, REDUCTASE COMPONENT - PSEUDOMONAS PUTIDA.
O53013 FERREDOXIN REDUCTASE ELECTRON TRANSFER COMPONENT - ESCHERICHIA COLI.
O86347 HYPOTHETICAL 33.5 KD PROTEIN - MYCOBACTERIUM TUBERCULOSIS.
P76081 FROM BASES 1449468 TO 1461540 (SECTION 126 OF 400) OF THE COMPLETE GENOME (SECTION 126 OF 400) - ESCHERICHIA COLI.
P77233 FERREDOXIN - ESCHERICHIA COLI.
P78476 TETRATRICOPEPTIDE REPEAT DOMAIN 3 (TPR REPEAT PROTEIN D) - HOMO SAPIENS (HUMAN).
P78477 TETRATRICOPEPTIDE REPEAT DOMAIN 3 (TPR REPEAT PROTEIN D) - HOMO SAPIENS (HUMAN).
P94680 TOLUENESULFONATE METHYL-MONOOXYGENASE REDUCTASE COMPONENT - COMAMONAS TESTOSTERONI (PSEUDOMONAS TESTOSTERONI).
P95533 ELECTRON TRANSFER PROTEIN - PSEUDOMONAS PUTIDA.
Q51603 2-HALOBENZOATE 1,2-DIOXYGENASE - BURKHOLDERIA CEPACIA (PSEUDOMONAS CEPACIA).
Q52574 OXIDOREDUCTASE - PSEUDOMONAS SP.
Q53028 REDUCTASE - NOCARDIA CORALLINA.
TTC3_HUMAN TETRATRICOPEPTIDE REPEAT DOMAIN 3 (TPR REPEAT PROTEIN D) - HOMO SAPIENS (HUMAN).
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