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(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2 = (5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2 = (5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2 = (5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
mechanism
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(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2 = (5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
a mechanism for CarC-catalyzed coupled epimerization and desaturation reactions is proposed
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(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2 = (5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
the contrathermodynamic epimerization of (3S,5S)-carbapenam-3-carboxylate to (3S,5R)-carbapenam-3-carboxylate is coupled at least to the binding of 2-oxoglutarate and it is probably coupled to the reduction of molecular oxygen and proceeds by way of radical abstraction at C-5. The presumed Fe(IV)=O species formed in these processes is required to drive the subsequent desaturation process
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(3R,5R)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: activity in presence of ascorbate is 22% compared to the activity with the natural substrate (3S,5S)-carbapenam-3-carboxylate, activity in absence of ascorbate is 86% compared to the activity with the natural substrate (3S,5S)-carbapenam-3-carboxylate in presence of ascorbate
Products: -
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(3R,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: activity in presence of ascorbate is less than 2% compared to the activity with the natural substrate (3S,5S)-carbapenam, activity in absence of ascorbate is 40% compared to the activity with the natural substrate (3S,5S)-carbapenam in presence of ascorbate
Products: -
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(3S,5R)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: activity in presence of ascorbate is 76% compared to the activity with the natural substrate (3S,5S)-carbapenam-3-carboxylate, activity in absence of ascorbate is 7% compared to the activity with the natural substrate (3S,5S)-carbapenam-3-carboxylate in presence of ascorbate
Products: -
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(3S,5S)-carbapen-2-am-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
(3S,5S)-carbapen-2-am-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: -
Products: -
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(3S,5S)-carbapen-2-am-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: the enzyme is involved in the biosynthesis of (5R)-carbapen-2-em-3-carboxylic acid the simplest structurally among the naturally occurring carbapenem beta-lactam antibiotics
Products: -
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(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: -
Products: -
?
(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: natural substrate. Activity with in absence of ascorbate is 2% compared to the activity in presence of ascorbate
Products: -
?
(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: the contrathermodynamic epimerization of (3S,5S)-carbapenam-3-carboxylate to (3S,5R)-carbapenam-3-carboxylate is coupled at least to the binding of 2-oxoglutarate and it is probably coupled to the reduction of molecular oxygen and proceeds by way of radical abstraction at C-5. The presumed Fe(IV)=O species formed in these processes is required to drive the subsequent desaturation process
Products: -
?
(3S,5S)-carbapenam-3-carboxylate + 2-oxoglutarate + O2
(5R)-carbapen-2-em-3-carboxylate + succinate + CO2 + H2O
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Substrates: quantum mechanics/molecular mechanics calculations uncover the reaction mechanism of CarC. The dioxygen binding site on metal is analyzed and it is identified that the Fe(IV)-oxo species has two potential orientations with the oxo group trans to either His101 or His251. The former is energetically unstable, which can rapidly isomerize into the latter by rotation of the oxo group. Arg279 plays important roles in regulating the dioxygen binding and assisting the isomerization of Fe(IV)-oxo species. The calculation results clearly support the stepwise C5-epimerization and C2/3-desaturation processes, involving two complete oxidative cycles. The epimerization process converts (3S,5S)-carbapenam to the initial product (3S,5R)-carbapenam, undergoing H5 atom abstraction by Fe(IV)-O species, inversion of the C5-radical, and reconstitution of the inverted C5-H bond by Tyr165. In the desaturation process, (3S,5R)-carbapenam rebinds the CarC active site with a new orientation different from what (3S,5S)-carbapenam does in the epimerization. In addition, the desaturation across C2-C3 occurs without involving any active site residue other than the Fe(IV)-O center. Whereas Tyr165 is not involved in the desaturation reaction, it plays a key role in binding (3S,5R)-carbapenam. (3S,5R)-Carbapenam is a substrate superior to its epimer (3S,5S)-carbapenam for CarC to produce (5R)-carbapenem by efficient desaturation. In addition, the substrate hydroxylations compete with the target epimerization and desaturation reaction
Products: -
?
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Sleeman, M.C.; Smith, P.; Kellam, B.; Chhabra, S.R.; Bycroft, B.W.; Schofield, C.J.
Biosynthesis of carbapenem antibiotics: new carbapenam substrates for carbapenem synthase (CarC)
Chembiochem
5
879-882
2004
Pectobacterium carotovorum
brenda
Stapon, A.; Li, R.; Townsend, C.A.
Synthesis of (3S,5R)-carbapenam-3-carboxylic acid and its role in carbapenem biosynthesis and the stereoinversion problem
J. Am. Chem. Soc.
125
15746-15747
2003
Pectobacterium carotovorum
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Stapon, A.; Li, R.; Townsend, C.A.
Carbapenem biosynthesis: confirmation of stereochemical assignments and the role of CarC in the ring stereoinversion process from L-proline
J. Am. Chem. Soc.
125
8486-8493
2003
Pectobacterium carotovorum
brenda
Topf, M.; Sandala, G.M.; Smith, D.M.; Schofield, C.J.; Easton, C.J.; Radom, L.
The unusual bifunctional catalysis of epimerization and desaturation by carbapenem synthase
J. Am. Chem. Soc.
126
9932-9933
2004
Pectobacterium carotovorum
brenda
Clifton, I.J.; Doan, L.X.; Sleeman, M.C.; Topf, M.; Suzuki, H.; Wilmouth, R.C.; Schofield, C.J.
Crystal structure of carbapenem synthase (CarC)
J. Biol. Chem.
278
20843-20850
2003
Pectobacterium carotovorum (Q9XB59)
brenda
Borowski, T.; Broclawik, E.; Schofield, C.J.; Siegbahn, P.E.
Epimerization and desaturation by carbapenem synthase (CarC). A hybrid DFT study
J. Comput. Chem.
27
740-748
2006
Pectobacterium carotovorum
brenda
McGowan, S.J.; Sebaihia, M.; Porter, L.E.; Stewart, G.S.; Williams, P.; Bycroft, B.W.; Salmond, G.P.
Analysis of bacterial carbapenem antibiotic production genes reveals a novel beta-lactam biosynthesis pathway
Mol. Microbiol.
22
415-426
1996
Pectobacterium carotovorum
brenda
Ma, G.; Zhu, W.; Su, H.; Cheng, N.; Liu, Y.
Uncoupled epimerization and desaturation by carbapenem synthase mechanistic insights from QM/MM studies
ACS Catal.
5
5556-5566
2015
Streptomyces cattleya
-
brenda
Chang, W.; Guo, Y.; Wang, C.; Butch, S.; Rosenzweig, A.; Boal, A.; Krebs, C.; Bollinger Jr., J.
Mechanism of the C5 stereoinversion reaction in the biosynthesis of carbapenem antibiotics
Science
343
1140-1144
2014
Pectobacterium carotovorum subsp. carotovorum (Q9XB59)
brenda
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