1.13.12.17: dichloroarcyriaflavin A synthase
This is an abbreviated version!
For detailed information about dichloroarcyriaflavin A synthase, go to the full flat file.
Reaction
Synonyms
CYP245A1, cytochrome P450 StaP, P450 StaP, StaP
ECTree
1.13.12.17 dichloroarcyriaflavin A synthaseAdvanced search results
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results (Substrates Products
Substrates Products on EC 1.13.12.17 - dichloroarcyriaflavin A synthase
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SUBSTRATE 
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
1,11-dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
1,11-dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
the reaction is catalyzed by enzyme StaP. StaC and RebC acting to direct the level of oxidation in the newly formed five-membered ring. Biosynthesis of the antitumor indolocarbazoles rebeccamycin and staurosporine by streptomycetes
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
1,11-dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
StaP, a cytochrome P450 enzyme, catalyzes an aryl-aryl bond-forming reaction to give a six-ring indolocarbazole scaffold, as well as mediating decarboxylation and oxidation of the putative dicarboxypyrrole moiety. This action requires two to four cycles of net two-electron substrate oxidation at the catalytic heme center. StaP produces three distinct products, differing in oxidation level. For the production of K252c from chromopyrrolic acid, a net four-electron oxidation is required. The generation ofarcyriaflavin A from chromopyrrolic acid requires an overall eight-electron oxidation. StaP is thus unusual in the apparent lack of oxidative control it possesses over the outcome of its catalytic turnover. Control of the overall oxidation route is provided by a second enzyme StaC, which imparts the net effect of directing the oxidation level of the pyrrole-derived ring. While StaP in isolation gives three aglycone forms, StaP and StaC turn over chromopyrrolic acid to give only a single product, K252c. Similarly, RebC (flavin-dependent hydroxylase) guides the turnover of chromopyrrolic acid toward the more highly oxidized maleimide-bearing aglycone, arcyriaflavin A
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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chromopyrrolic acid oxidation by cytochrome P450 StaP is a key process in the biosynthesis of antitumor drugs
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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electron transfer activation of chromopyrrolic acid by cytochrome P450 en route to the formation of an antitumor indolocarbazole derivative
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?
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
StaP/RebP is simply responsible for the two-electron intramolecular aryl-aryl coupling of dichlorochromopyrrolate to give the six-ring intermediate 5,7-dicarboxy-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole with all subsequent steps occurring nonenzymatically in solution. The study on the nonenzymatic steps following StaP-mediated aryl-aryl bond formation corroborates the proposed role of RebC (and by extension StaC) in intercepting and redirecting intermediates en route to the aglycones, K252c, 7-hydroxy-K252c, and arcyriaflavin A
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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the hydrogen-bonding machinery of the pocket deprotonates the carboxylic acid groups of chromopyrrolic acid, while the nearby His250 residue and the crystal waters, Wat644 and Wat789, assist the doubly deprotonated chromopyrrolic acid to transfer electron density to compound I. Hence, chromopyrrolic acid is activated toward proton-coupled electron transfer that sets the entire mechanism in motion. The ensuing mechanism involves a step of C-C bond formation coupled to a second electron transfer, four proton-transfer and tautomerization steps, and four steps where Wat644 and Wat789 move about and mediate these events. The water diad is the minimal requisite element that endows StaP with function
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dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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?
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
staurosporine biosynthesis
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?
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
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?
dichlorochromopyrrolate + 4 O2 + 4 NADH + 4 H+
dichloroarcyriaflavin A + 2 CO2 + 6 H2O + 4 NAD+
staurosporine biosynthesis
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?
