KEGG ENZYME: 1.14.13.250

ENZYME: 1.14.13.250

Entry

EC 1.14.13.250              Enzyme

Name

nitrosourea synthase;
sznF (gene name);
StzF

Class

Oxidoreductases;
Acting on paired donors, with incorporation or reduction of molecular oxygen;
With NADH or NADPH as one donor, and incorporation of one atom of oxygen into the other donor

Sysname

Nomega-methyl-L-arginine,NADH:oxygen oxidoreductase (Ndelta-hydroxy-Nomega-methyl-Nomega-nitroso-L-citrulline-forming)

Reaction(IUBMB)

Nomega-methyl-L-arginine + 2 NADH + 2 H+ + 3 O2 = Ndelta-hydroxy-Nomega-methyl-Nomega-nitroso-L-citrulline + 2 NAD+ + 3 H2O (overall reaction) [RN:R12921];
(1a) Nomega-methyl-L-arginine + NADH + H+ + O2 = Ndelta-hydroxy-Nomega-methyl-L-arginine + NAD+ + H2O [RN:R12922];
(1b) Ndelta-hydroxy-Nomega-methyl-L-arginine + NADH + H+ + O2 = Ndelta,Nomega'-dihydroxy-Nomega-methyl-L-arginine + NAD+ + H2O [RN:R12923];
(1c) Ndelta,Nomega'-dihydroxy-Nomega-methyl-L-arginine + O2 = Ndelta-hydroxy-Nomega-methyl-Nomega-nitroso-L-citrulline + H2O [RN:R12924]

Reaction(KEGG)

R12921 R12922 R12923 R12924

Substrate

N(omega)-Methyl-L-arginine [CPD:C03884];
NADH [CPD:C00004];
H+ [CPD:C00080];
O2 [CPD:C00007];
N(delta)-Hydroxy-N(omega)-methyl-L-arginine [CPD:C22419];
N(delta),N'(omega)-Dihydroxy-N(omega)-methyl-L-arginine [CPD:C22420]

Product

N(delta)-Hydroxy-N(omega)-methyl-N(omega)-nitroso-L-citrulline [CPD:C22422];
NAD+ [CPD:C00003];
H2O [CPD:C00001];
N(delta)-Hydroxy-N(omega)-methyl-L-arginine [CPD:C22419];
N(delta),N'(omega)-Dihydroxy-N(omega)-methyl-L-arginine [CPD:C22420]

Comment

The enzyme, characterized from the bacterium Streptomyces achromogenes subsp. streptozoticus, catalyses a complex multi-step reaction during the biosynthesis of the glucosamine-nitrosourea antibiotic streptozotocin. The overall reaction is an oxidative rearrangement of the guanidine group of Nomega-methyl-L-arginine, generating an N-nitrosourea product. The enzyme hydroxylates its substrate at the Ndelta position, followed by a second hydroxylation at the Nomega' position. It then catalyses an oxidative rearrangement to form Ndelta-hydroxy-Nomega-methyl-Nomega-nitroso-L-citrulline. This product is unstable, and degrades non-enzymically into nitric oxide and the denitrosated product Ndelta-hydroxy-Nomega-methyl-L-citrulline. The enzyme contains two active sites, each of which utilizes a different iron-containing cofactor.

History

EC 1.14.13.250 created 2021

Orthology

K25564

nitrosourea synthase

Genes

SFO:	Z042_15360

GQU:	AWC35_21535

XBV:

XBW1_2298

PVR:	PverR02_23035

POI:	BOP93_18675

PMED:

E3Z27_00380

PEZ:	HWQ56_06500

LPO:

LPO_2543

LPP:

lpp2434

CSA:

Csal_0745

GSN:	YC6258_05112

MIND:

mvi_61470

ABF:	AMK58_02765

AARE:

D3093_33255

MSD:	MYSTI_06152

SUR:	STAUR_6517

CFUS:

CYFUS_008378

SCL:

sce5189

BTB:	BMB171_C3897

MDR:	MDOR_11510

SLD:

T261_2090

SGV:	B1H19_08385

SNK:	CP967_01130

SPAD:

DVK44_08260

SNF:	JYK04_04420

SHK:	J2N69_18850

SDD:	D9753_22505

SHAU:

K9S39_40215

SLAI:

P8A22_00155

KIT:	CFP65_3101

ACTW:

F7P10_20360

ACIR:

OG979_18060 OG979_18075

SPIQ:

OHA34_21485 OHA34_21500

ACTQ:

OG417_44345 OG417_44360

KAL:	KALB_2732 KALB_6236

PLK:	CIK06_02470

CYJ:	Cyan7822_5656

» show all

Reference

1 [PMID:30728519]

Authors

Ng TL, Rohac R, Mitchell AJ, Boal AK, Balskus EP.

Title

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin.

Journal

Nature 566:94-99 (2019)
DOI:10.1038/s41586-019-0894-z

Sequence

[ag:QBA82202]

Reference

2 [PMID:30763082]

Authors

He HY, Henderson AC, Du YL, Ryan KS.

Title

Two-Enzyme Pathway Links l-Arginine to Nitric Oxide in N-Nitroso Biosynthesis.

Journal

J Am Chem Soc 141:4026-4033 (2019)
DOI:10.1021/jacs.8b13049

Sequence

[ag:QBF29330]

Reference

3 [PMID:32511919]

Authors

McBride MJ, Sil D, Ng TL, Crooke AM, Kenney GE, Tysoe CR, Zhang B, Balskus EP, Boal AK, Krebs C, Bollinger JM Jr.

Title

A Peroxodiiron(III/III) Intermediate Mediating Both N-Hydroxylation Steps in Biosynthesis of the N-Nitrosourea Pharmacophore of Streptozotocin by the Multi-domain Metalloenzyme SznF.

Journal

J Am Chem Soc 142:11818-11828 (2020)
DOI:10.1021/jacs.0c03431

Reference

4 [PMID:33468680]

Authors

McBride MJ, Pope SR, Hu K, Okafor CD, Balskus EP, Bollinger JM Jr, Boal AK.

Title

Structure and assembly of the diiron cofactor in the heme-oxygenase-like domain of the N-nitrosourea-producing enzyme SznF.

Journal

Proc Natl Acad Sci U S A 118:e2015931118 (2021)
DOI:10.1073/pnas.2015931118

Reference

5 [PMID:34004115]

Authors

Wang J, Wang X, Ouyang Q, Liu W, Shan J, Tan H, Li X, Chen G.

Title

N-Nitrosation Mechanism Catalyzed by Non-heme Iron-Containing Enzyme SznF Involving Intramolecular Oxidative Rearrangement.

Journal

Inorg Chem 60:7719-7731 (2021)
DOI:10.1021/acs.inorgchem.1c00057

Other DBs

ExplorEnz - The Enzyme Database:

1.14.13.250

IUBMB Enzyme Nomenclature:

1.14.13.250

ExPASy - ENZYME nomenclature database:

1.14.13.250

BRENDA, the Enzyme Database:

1.14.13.250

All links

Chemical substance (9)   
   KEGG COMPOUND (9)   
Chemical reaction (4)   
   KEGG REACTION (4)   
Gene (44)   
   KEGG ORTHOLOGY (1)   
   KEGG GENES (43)   
Protein sequence (2)   
   UniProt (1)   
   SWISS-PROT (1)   
Protein domain (4)   
   InterPro (4)   
All databases (63)   

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