P0A512 (CP51_MYCTU) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Lanosterol 14-alpha demethylase
EC=1.14.13.70

Alternative name(s):
CYPLI
Cytochrome P450 51
Cytochrome P450-14DM
Cytochrome P450-LIA1
Sterol 14-alpha demethylase

Gene names

Name:	cyp51
Ordered Locus Names:	Rv0764c, MT0788
ORF Names:	MTCY369.09c

Organism

Mycobacterium tuberculosis [Reference proteome] [HAMAP]

Taxonomic identifier

1773 [NCBI]

Taxonomic lineage

cellular organisms › Bacteria › Actinobacteria › Actinobacteria › Actinobacteridae › Actinomycetales › Corynebacterineae › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis complex

Protein attributes

Sequence length	451 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Its precise biological substrate is not known. Catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol. Ref.3 Ref.4
Catalytic activity	A 14-alpha-methylsteroid + 3 O2 + 3 NADPH = a Delta(14)-steroid + formate + 3 NADP+ + 4 H2O. Ref.4
Cofactor	Heme group. Ref.3
Enzyme regulation	Inhibited by alpha-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA) and 4,4'-dihydroxybenzophenone (DHBP). Ref.9
Pathway	Steroid biosynthesis; zymosterol biosynthesis; zymosterol from lanosterol: step 1/6.
Subunit structure	Homodimer. Ref.9
Subcellular location	Cytoplasm Probable.
Sequence similarities	Belongs to the cytochrome P450 family.

Ontologies

Keywords
Biological process	Lipid biosynthesis Lipid metabolism Steroid biosynthesis Steroid metabolism Sterol biosynthesis Sterol metabolism
Cellular component	Cytoplasm
Ligand	Heme Iron Metal-binding NADP
Molecular function	Monooxygenase Oxidoreductase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	sterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW sterol metabolic process Inferred from direct assay PubMed 16819841. Source: MTBBASE
Cellular_component	cytosol Inferred from direct assay Ref.3. Source: MTBBASE
Molecular_function	electron carrier activity Inferred from electronic annotation. Source: InterPro heme binding Inferred from direct assay Ref.3. Source: MTBBASE iron ion binding Inferred from electronic annotation. Source: InterPro sterol 14-demethylase activity Inferred from direct assay Ref.4PubMed 16819841. Source: MTBBASE
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 451

451

Lanosterol 14-alpha demethylase

PRO_0000052017

Sites

Metal binding

394

1

Iron (heme axial ligand)

Binding site

72

1

Heme

Binding site

76

1

Heme

Binding site

97

1

Heme

Binding site

259

1

Substrate

Binding site

326

1

Heme

Binding site

392

1

Heme

Binding site

433

1

Substrate

Secondary structure

1

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451

Helix Strand Turn

Details...

Helix

19 – 22

4

Helix

26 – 37

12

Beta strand

39 – 45

7

Beta strand

48 – 53

6

Helix

56 – 64

9

Turn

67 – 69

3

Beta strand

70 – 72

3

Helix

73 – 75

3

Helix

77 – 79

3

Helix

80 – 83

4

Helix

96 – 100

5

Helix

103 – 105

3

Helix

107 – 125

19

Beta strand

130 – 135

6

Helix

136 – 152

17

Helix

155 – 158

4

Helix

163 – 173

11

Helix

178 – 181

4

Helix

189 – 214

26

Beta strand

220 – 222

3

Helix

225 – 231

7

Beta strand

237 – 240

4

Helix

243 – 274

32

Helix

276 – 289

14

Helix

290 – 292

3

Helix

296 – 299

4

Helix

305 – 317

13

Beta strand

324 – 328

5

Beta strand

332 – 334

3

Beta strand

337 – 339

3

Beta strand

344 – 347

4

Helix

349 – 352

4

Turn

356 – 358

3

Beta strand

359 – 361

3

Helix

367 – 370

4

Turn

372 – 374

3

Helix

376 – 379

4

Turn

381 – 383

3

Helix

390 – 392

3

Helix

397 – 414

18

Beta strand

415 – 421

7

Helix

423 – 425

3

Beta strand

431 – 434

4

Beta strand

442 – 447

6

Sequences

	Sequence		Length	Mass (Da)
	P0A512 [UniParc]. Last modified March 15, 2005. Version 1. Checksum: B3D671EA9542A57B	FASTA	451	50,878
	10 20 30 40 50 60 MSAVALPRVS GGHDEHGHLE EFRTDPIGLM QRVRDECGDV GTFQLAGKQV VLLSGSHANE 70 80 90 100 110 120 FFFRAGDDDL DQAKAYPFMT PIFGEGVVFD ASPERRKEML HNAALRGEQM KGHAATIEDQ 130 140 150 160 170 180 VRRMIADWGE AGEIDLLDFF AELTIYTSSA CLIGKKFRDQ LDGRFAKLYH ELERGTDPLA 190 200 210 220 230 240 YVDPYLPIES FRRRDEARNG LVALVADIMN GRIANPPTDK SDRDMLDVLI AVKAETGTPR 250 260 270 280 290 300 FSADEITGMF ISMMFAGHHT SSGTASWTLI ELMRHRDAYA AVIDELDELY GDGRSVSFHA 310 320 330 340 350 360 LRQIPQLENV LKETLRLHPP LIILMRVAKG EFEVQGHRIH EGDLVAASPA ISNRIPEDFP 370 380 390 400 410 420 DPHDFVPARY EQPRQEDLLN RWTWIPFGAG RHRCVGAAFA IMQIKAIFSV LLREYEFEMA 430 440 450 QPPESYRNDH SKMVVQLAQP ACVRYRRRTG V

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence." Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K. , Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K., Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J., Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S., Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S., Barrell B.G. Nature 393:537-544(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: ATCC 25618 / H37Rv.
[2]	"Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains." Fleischmann R.D., Alland D., Eisen J.A., Carpenter L., White O., Peterson J.D., DeBoy R.T., Dodson R.J., Gwinn M.L., Haft D.H., Hickey E.K., Kolonay J.F., Nelson W.C., Umayam L.A., Ermolaeva M.D., Salzberg S.L., Delcher A., Utterback T.R. , Weidman J.F., Khouri H.M., Gill J., Mikula A., Bishai W., Jacobs W.R. Jr., Venter J.C., Fraser C.M. J. Bacteriol. 184:5479-5490(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: CDC 1551 / Oshkosh.
[3]	"CYP51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51." Aoyama Y., Horiuchi T., Gotoh O., Noshiro M., Yoshida Y. J. Biochem. 124:694-696(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A P450 CYTOCHROME, COFACTOR.
[4]	"Characterization and catalytic properties of the sterol 14 alpha-demethylase from Mycobacterium tuberculosis." Bellamine A., Mangla A.T., Nes W.D., Waterman M.R. Proc. Natl. Acad. Sci. U.S.A. 96:8937-8942(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS LANOSTEROL 14-ALPHA DEMETHYLASE, CATALYTIC ACTIVITY.
[5]	"Structural requirements for substrate recognition of Mycobacterium tuberculosis 14alpha-demethylase: implications for sterol biosynthesis." Bellamine A., Mangla A.T., Dennis A.L., Nes W.D., Waterman M.R. J. Lipid Res. 42:128-136(2001) [PubMed] [Europe PMC] [Abstract] Cited for: SUBSTRATE SPECIFICITY.
[6]	"Crystal structure of cytochrome P450 14 alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors." Podust L.M., Poulos T.L., Waterman M.R. Proc. Natl. Acad. Sci. U.S.A. 98:3068-3073(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN COMPLEX WITH HEME AND SUBSTRATE ANALOGS.
[7]	"Estriol bound and ligand-free structures of sterol 14alpha-demethylase." Podust L.M., Yermalitskaya L.V., Lepesheva G.I., Podust V.N., Dalmasso E.A., Waterman M.R. Structure 12:1937-1945(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) IN COMPLEX WITH HEME AND ESTRIOL.
[8]	"Crystal structure analysis of the C37L/C151T/C442A-triple mutant of CYP51 from Mycobacterium tuberculosis." Podust L.M., Yermalitskaya L.V., Kim Y., Waterman M.R. Submitted (JUL-2004) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.01 ANGSTROMS) IN COMPLEX WITH HEME, MUTAGENESIS.
[9]	"Small-molecule scaffolds for CYP51 inhibitors identified by high-throughput screening and defined by X-ray crystallography." Podust L.M., von Kries J.P., Eddine A.N., Kim Y., Yermalitskaya L.V., Kuehne R., Ouellet H., Warrier T., Altekoster M., Lee J.S., Rademann J., Oschkinat H., Kaufmann S.H., Waterman M.R. Antimicrob. Agents Chemother. 51:3915-3923(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) IN COMPLEX WITH HEME AND SUBSTRATE ANALOGS, ENZYME REGULATION, SUBUNIT.
[10]	"X-ray structure of 4,4'-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51)." Eddine A.N., von Kries J.P., Podust M.V., Warrier T., Kaufmann S.H., Podust L.M. J. Biol. Chem. 283:15152-15159(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) IN COMPLEX WITH HEME AND SUBSTRATE ANALOGS.
[11]	"Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit." Chen C.K., Doyle P.S., Yermalitskaya L.V., Mackey Z.B., Ang K.K., McKerrow J.H., Podust L.M. PLoS Negl. Trop. Dis. 3:E372-E372(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) IN COMPLEX WITH HEME AND SUBSTRATE ANALOGS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

BX842574 Genomic DNA. Translation: CAB02394.1.
AE000516 Genomic DNA. Translation: AAK45030.1.
AL123456 Genomic DNA. Translation: CCP43511.1.

PIR

G70706.

RefSeq

NP_215278.1. NC_000962.3.
NP_335216.1. NC_002755.2.
YP_006514111.1. NC_018143.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E9X	X-ray	2.10	A	1-451	[»]
1EA1	X-ray	2.21	A	1-451	[»]
1H5Z	X-ray	2.05	A	1-451	[»]
1U13	X-ray	2.01	A	1-451	[»]
1X8V	X-ray	1.55	A	1-451	[»]
2BZ9	X-ray	2.21	A/B	1-451	[»]
2CI0	X-ray	1.53	A	1-451	[»]
2CIB	X-ray	1.50	A	1-451	[»]
2VKU	X-ray	1.95	A	1-451	[»]
2W09	X-ray	1.57	A	1-451	[»]
2W0A	X-ray	1.60	A	1-451	[»]
2W0B	X-ray	1.56	A	1-451	[»]

ProteinModelPortal

P0A512.

SMR

P0A512. Positions 6-449.

ModBase

Search...

Protein-protein interaction databases

STRING

83332.Rv0764c.

Proteomic databases

PRIDE

P0A512.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

EnsemblBacteria

AAK45030; AAK45030; MT0788.

GeneID

13318658.
888819.
926091.

KEGG

mtc:MT0788.
mtu:Rv0764c.
mtv:RVBD_0764c.

PATRIC

18123476. VBIMycTub22151_0866.

Organism-specific databases

TubercuList

Rv0764c.

Phylogenomic databases

eggNOG

COG2124.

HOGENOM

HOG000042780.

KO

K05917.

OMA

WGDEGEI.

ProtClustDB

CLSK790721.

Enzyme and pathway databases

UniPathway

UPA00770; UER00754.

Family and domain databases

Gene3D

1.10.630.10. 1 hit.

InterPro

IPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002403. Cyt_P450_E_grp-IV.
[Graphical view]

Pfam

PF00067. p450. 1 hit.
[Graphical view]

PRINTS

PR00465. EP450IV.
PR00385. P450.

SUPFAM

SSF48264. Cytochrome_P450. 1 hit.

PROSITE

PS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P0A512.

ChEMBL

CHEMBL5090.

DrugBank

DB04573. Estriol.

EvolutionaryTrace

P0A512.

Entry information

Entry name

CP51_MYCTU

Accession

Primary (citable) accession number: P0A512
Secondary accession number(s): L0T4U1, P77901

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 15, 2005
Last sequence update:	March 15, 2005
Last modified:	May 1, 2013
This is version 76 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Prokaryotic Protein Annotation Program