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The taxonomic range for the selected organisms is: Streptomyces viridochromogenes
The enzyme appears in selected viruses and cellular organisms
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(2R)-hydroxypropylphosphonate + O2
2-oxopropylphosphonate + hydroxymethylphosphonate + acetate
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substrate partitions between conversion to 2-oxopropylphosphonate and hydroxymethylphosphonate
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(R)-2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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product is almost racemic
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(S)-2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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product is almost racemic
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1-hydroxy-2,2,2-trifluoroethylphosphonate + O2
trifluoroacetylphosphonate
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1-hydroxyethylphosphonate + O2
acetylphosphate
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
hydroxymethylphosphonate + O2
phosphate + formate
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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additional information
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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ir
2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
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all four electrons required for reduction of O2 are provided by the substrate. Occurence of an intermediate species in which oxygen derived from O2 exchanges with water
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
catalytic cycle is based on concatenated bifurcations. The first bifurcation is based on the abstraction of hydrogen atoms from the substrate, which leads to a distal or proximal hydroperoxo species Fe-OOH or Fe-(OH)O. The second and the third bifurcations refer to the carbon-carbon bond cleavage reaction achieved through a tridentate intermediate, or employing a proton-shuttle assisted mechanism, in which the residue Glu176 or the FeIV O group serves as a general base. The reaction directions seem to be tunable and show significant environment dependence
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
in the reaction mechanism water molecules serve as an oxygen source in the generation of mononuclear nonheme iron oxo complexes, taking part in the catalytic cycle before the carbon-carbon bond cleavage process. After the dioxygen is bound to the iron center, the dioxygen-bound species Fe-O2 is generated. The abstraction of hydrogen atom from the substrate leads to a distal or proximal hydroperoxo species Fe(III)-OOH. This is the rate-limiting step, which has an energy barrier of 21 and 18 kcal/mol for distal and proximal H-abstraction processes, respectively. The second step is the cleavage of the O-O bond, and the carbon-carbon bond is broken subsequently. In this step, a tridentate binding species and a Fe(IV) sigmaO species are important intermediates to break the carbon-carbon bond. In the third step, the formic acid and the intermediate CH2PO2(OH)- radical are generated. Finally, 2-hydroxyethylphosphonate is converted to hydroxymethylphosphonate, and the formate or formic acid is formed
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
mechanism involves removal of the pro-S hydrogen at C2 and the loss of stereochemical information at C1. Thus, the hydroperoxylation mechanism, previously proposed as the product of a Criegee rearrangement, cannot be operational for conversion of 2-hydroxyethylphosphonate
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2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
an irreversible step involving O2
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ir
2-hydroxyethylphosphonate + O2
hydroxymethylphosphonate + formate
the reaction proceeds via a transient iron(IV)-oxo (ferryl) complex, the mechanism involves activation of an O-H bond by the ferryl complex. Maximal accumulation of the intermediate requires both the presence of deuterium in the substrate and, importantly, the use of 2H2O as solvent
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additional information
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proper binding of 2-hydroxyethylphosphonate is important for O2 activation and the enzyme uses a compulsory binding order with 2-hydroxyethylphosphonate binding before O2. In the mechanism, a hydroperoxylation process is followed by a Criegee rearrangement and hydrolysis to form hydroxymethylphosphonate. Thereafter, the P-C bond in the product can be transiently broken, generating phosphite and formaldehyde in the active site of the enzyme. If the formaldehyde is able to rotate along the C=O bond, then phosphite can attack either face of the carbonyl group resulting in a loss of stereochemistry
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additional information
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reaction starts with H-abstraction from the C2 position of 2-hydroxyethylphosphonate by a ferric superoxide-type intermediate. The resultant Fe(II)-OOH intermediate may follow either a hydroperoxylation or hydroxylation pathway, the former process being energetically more favorable. In the hydroperoxylation pathway, a ferrous-alkylhydroperoxo intermediate is formed, and then its O-O bond is homolytically cleaved to yield a complex of ferric hydroxide with a gem-diol radical. Subsequent C-C bond cleavage within the gem-diol leads to formation of an R-CH2 radical species and one of the two products, i.e., formic acid. The R-CH2 radical then intramolecularly forms a C-O bond with the ferric hydroxide to provide the other product, hydroxymethylphosphonate. The overall reaction pathway requires ferric superoxide and ferric hydroxide intermediates
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additional information
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results provide strong support for a mechanism that proceeds by hydroperoxylation followed by a Criegee rearrangement with a phosphorus-based migrating group and requires that the O-O bond of molecular oxygen is not cleaved prior to substrate activation. No substrate: O-formyl-hydroxymethylphosphonate, (2S)-hydroxypropylphosphonate
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additional information
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HEPD oxidizes a relatively unactivated substrate that cannot easily facilitate O2 activation. 2-Hydroxyethylphosphonate does not contain a thiol group that upon binding to the iron can activate it for catalysis, nor does it contain an 2-oxo acid functionality
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E176A
site-directed mutagenesis, the mutant enzyme shows similar activity as the wild-type enzyme. Like the wild-type enzyme, the mutant HEPD-E176A produces hydroxymethylphosphonate and formate as its only detectable products upon incubation with Fe(II), hydroxyethylphosphonate, and O2
K16A
loss of enzymic activity
R90A
large decrease in ratio kcat/Km, mutant cannot be saturated in O2
R90K
slight decrease in ratio kcat/Km
Y98F
large decrease in ratio kcat/Km, mutant cannot be saturated in O2. Mutant produces methylphosphonate as a minor side product
E176H
site-directed mutagenesis, the mutant is bifunctional exhibiting the activity of both 2-hydroxyethylphosphonate dioxygenase (HEPD) and methylphosphonate synthase (MPnS, EC 1.13.11.73). The product distribution of the mutant is sensitive to a substrate isotope effect, consistent with an isotope-sensitive branching mechanism involving a common intermediate. The introduced histidine does not coordinate the active site metal, unlike the iron-binding glutamate it replaces. More HEPD activity is observed when the reaction is carried out with (R)-2-[2-2H1]-hydroxyethylphosphonate
E176H
the mutant catalyzes the transformation of 2-hydroxypropylphosphonate to methylphosphonate
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Peck, S.C.; Cooke, H.A.; Cicchillo, R.M.; Malova, P.; Hammerschmidt, F.; Nair, S.K.; van der Donk, W.A.
Mechanism and substrate recognition of 2-hydroxyethylphosphonate dioxygenase
Biochemistry
50
6598-6605
2011
Streptomyces viridochromogenes (Q5IW40)
brenda
Whitteck, J.T.; Cicchillo, R.M.; van der Donk, W.A.
Hydroperoxylation by hydroxyethylphosphonate dioxygenase
J. Am. Chem. Soc.
131
16225-16232
2009
Streptomyces viridochromogenes (Q5IW40)
brenda
Hirao, H.; Morokuma, K.
Ferric superoxide and ferric hydroxide are used in the catalytic mechanism of hydroxyethylphosphonate dioxygenase: a density functional theory investigation
J. Am. Chem. Soc.
132
17901-17909
2010
Streptomyces viridochromogenes (Q5IW40)
brenda
Whitteck, J.T.; Malova, P.; Peck, S.C.; Cicchillo, R.M.; Hammerschmidt, F.; van der Donk, W.A.
On the stereochemistry of 2-hydroxyethylphosphonate dioxygenase
J. Am. Chem. Soc.
133
4236-4239
2011
Streptomyces viridochromogenes (Q5IW40)
brenda
Du, L.; Gao, J.; Liu, Y.; Liu, C.
Water-dependent reaction pathways: an essential factor for the catalysis in HEPD enzyme
J. Phys. Chem. B
116
11837-11844
2012
Streptomyces viridochromogenes (Q5IW40)
brenda
Cicchillo, R.M.; Zhang, H.; Blodgett, J.A.; Whitteck, J.T.; Li, G.; Nair, S.K.; van der Donk, W.A.; Metcalf, W.W.
An unusual carbon-carbon bond cleavage reaction during phosphinothricin biosynthesis
Nature
459
871-874
2009
Streptomyces viridochromogenes (Q5IW40)
brenda
Peck, S.C.; Chekan, J.R.; Ulrich, E.C.; Nair, S.K.; van der Donk, W.A.
A common late-stage intermediate in catalysis by 2-hydroxyethyl-phosphonate dioxygenase and methylphosphonate synthase
J. Am. Chem. Soc.
137
3217-3220
2015
Streptomyces viridochromogenes (Q5IW40), Streptomyces viridochromogenes DSM 40736 (Q5IW40)
brenda
Peck, S.C.; Wang, C.; Dassama, L.M.; Zhang, B.; Guo, Y.; Rajakovich, L.J.; Bollinger, J.M.; Krebs, C.; van der Donk, W.A.
O-H activation by an unexpected ferryl intermediate during catalysis by 2-hydroxyethylphosphonate dioxygenase
J. Am. Chem. Soc.
139
2045-2052
2017
Streptomyces viridochromogenes (Q5IW40), Streptomyces viridochromogenes DSM 40736 (Q5IW40)
brenda
Peck, S.C.; van der Donk, W.A.
Go it alone four-electron oxidations by mononuclear non-heme iron enzymes
J. Biol. Inorg. Chem.
22
381-394
2017
Streptomyces viridochromogenes (Q5IW40), Streptomyces viridochromogenes DSM 40736 (Q5IW40)
brenda
Li, Y.; Wang, X.; Zhang, R.; Wang, J.; Yang, Z.; Du, L.; Tang, X.; Zhang, Q.; Wang, W.
Computational evidence for the enzymatic transformation of 2-hydroxypropylphosphonate to methylphosphonate
ACS Earth Space Chem.
2
888-894
2018
Streptomyces viridochromogenes (Q5IW40), Streptomyces viridochromogenes DSM 40736 (Q5IW40)
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brenda
Wang, B.; Cao, Z.; Rovira, C.; Song, J.; Shaik, S.
Fenton-derived OH radicals enable the MPnS enzyme to convert 2-hydroxyethylphosphonate to methylphosphonate Insights from ab initio QM/MM MD simulations
J. Am. Chem. Soc.
141
9284-9291
2019
Streptomyces viridochromogenes
brenda