Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide.

Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Research Abstract Details 

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Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Abstract Text:

Ling Sun,Chong S Chen,David J Waxman,Hong Liu,James R Halpert,Santosh Kumar,

Based on recent directed evolution of P450 2B1, six P450 2B11 mutants at three positions were created in an N-terminal modified construct termed P450 2B11dH and characterized for enzyme catalysis using five substrates. Mutant I209A demonstrated a 3.2-fold enhanced k(cat)/K(m) for 7-ethoxy-4-trifluoromethylcourmarin O-deethylation, largely due to a dramatic decrease in K(m) (0.72 microM vs. 18 microM). I209A also demonstrated enhanced selectivity for testosterone 16beta-hydroxylation over 16alpha-hydroxylation. In contrast, V183L showed a 4-fold increased k(cat) for 7-benzyloxyresorufin debenzylation and a 4.7-fold increased k(cat)/K(m) for testosterone 16alpha-hydroxylation. V183L also displayed a 1.7-fold higher k(cat)/K(m) than P450 2B11dH with the anti-cancer prodrugs cyclophosphamide and ifosfamide, resulting from a approximately 4-fold decrease in K(m). Introduction of the V183L mutation into full-length P450 2B11 did not enhance the k(cat)/K(m). Overall, the re-engineered P450 2B11dH enzymes exhibited enhanced catalytic efficiency with several substrates including the anti-cancer prodrugs.

Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Publishing Authors By Initials

L Sun,CS Chen,DJ Waxman,H Liu,JR Halpert,S Kumar,

For similar polycyclic compounds: steroids: androstanes: androstenes: androstenols: testosterone research abstracts see: polycyclic compounds: steroids: androstanes: androstenes: androstenols: testosterone research

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Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Archives of biochemistry and biophysics

VOLUME: 458

Page Numbers: 167-74

Journal Abbreviation: Arch. Biochem. Biophys.

ISSN: 0003-9861

DAY: 8

MONTH: 01

YEAR: 2007

Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 372430

Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Keywords Mesh Terms:

KEYWORDS: Testosterone

MESH TERMS: metabolism

Chemical & Substance for Abstract: Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide. Information

Substance Name: Aryl Hydrocarbon Hydroxylases

Registry Number: EC 1.14.14.1

Grant and Affiliation Information for Re-engineering cytochrome P450 2B11dH for enhanced metabolism of several substrates including the anti-cancer prodrugs cyclophosphamide and ifosfamide.

AFFILIATION: Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1031, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: R01 ES003619-22

ACRONYM: ES

MEDLINETA: Arch Biochem Biophys

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