Arthropod P450 Dokuwiki

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====== First steps of the P450 catalytic cycle ======


[[https://doi.org/10.1021/bi9719399|Guengerich and Johnson, 1979]] challenged the common dogma that substrate binding is the first step, followed by reduction. They showed that in many cases reduction can occur before substrate binding, leading to an alternative view of the sequence of events: {{ ::guengerichfig2.png?400 |}}


These authors conclude that "nevertheless, substrate binding probably is the first step in most P450 cycles, at least under laboratory experimental conditions in which it is in excess, simply because substrate binding is faster than reduction. For instance, if substrate binding occurs at a diffusion-limited rate of ≈ 10<sup>8</sup> M<sup>-1</sup> s<sup>-1</sup>, then at a substrate concentration of 10<sup>-6</sup> M the on-rate is ≈ 100 s<sup>-1</sup>, or 6000 min<sup>-1</sup>, very competitive with reduction. In some cases substrate binding may be needed for reduction, presumably to shift the P450 to a conformation more favorable for reduction. There is no reason that substrate binding cannot occur later in the reaction cycle, if not required for reduction. In the case of reaction supported by oxygen surrogates, substrate binding may even be preceeded by the formation of an oxygenating species".

Most interestingly, Guengerich and Johnson compared reduction rates and testosterone hydroxylation rates of CYP3A4 under various experimental conditions. It is very likely that these observations on human CYP3A4 can serve to warn against bold comparisons of reaction rates for arthropod P450s in various [[functions|expression]] systems. {{ ::guengerichtable5.png?600 |}}