KEGG   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)
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)-Hydroxy-N(omega)-hydroxy-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)-Hydroxy-N(omega)-hydroxy-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
SFOZ042_15360
GQUAWC35_21535
XBVXBW1_2298
PVRPverR02_23035
POIBOP93_18675
PMEDE3Z27_00380
PEZHWQ56_06500
LPOLPO_2543
LPPlpp2434
CSACsal_0745
GSNYC6258_05112
MSDMYSTI_06152
SURSTAUR_6517
CFUSCYFUS_008378
SCLsce5189
MINDmvi_61470
ABFAMK58_02765
BTBBMB171_C3897
MDRMDOR_11510
SLDT261_2090
SGVB1H19_08385
SNKCP967_01130
SPADDVK44_08260
SNFJYK04_04420
SHKJ2N69_18850
SDDD9753_22505
KITCFP65_3101
ACTWF7P10_20360
KALKALB_2732 KALB_6236
PLKCIK06_02470
CYJCyan7822_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
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
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

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