Early role during chemical evolution for cytochrome P450 in oxygen detoxification

Wickramasinghe, Rohan H.; Villee, Claude A.

doi:10.1038/256509a0

Cited by 49 publications

(11 citation statements)

References 12 publications

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“…It has been suggested that the earliest role of P450 was as a defence mechanism in order to detoxify oxygen and its reactive intermediates, which formed during the simple processes of cellular metabolism and photosynthesis in the primitive cell [15], but other more primitive CYP forms may have been involved in this. The reason for the substrate selectivity di¡erence observed for the plant as opposed to human/fungal CYP51s presumably re£ects the early divergence of the sterol biosynthetic pathway in the plant kingdom.…”

Section: Metabolism Of Obtusifoliolmentioning

confidence: 99%

Molecular diversity of sterol 14α‐demethylase substrates in plants, fungi and humans

Lamb

Kelly

1998

FEBS Letters

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Metabolism of lanosterol (LAN), , dihydrolanosterol (DHL) and obtusifoliol (OBT) by purified human, plant (Sorghum bicolor) and fungal (Candida albicans) sterol 14K Kdemethylase (CYP51; P450 IRhw ) reconstituted with NADPH cytochrome P450 reductases was studied in order to elucidate the substrate specificity and sterol stereo-and regio-structural requirements for optimal CYP51 activity. Both human and C. albicans CYP51 could catalyse 14K K-demethylation of each substrate with varying levels of activity, but having slightly higher activity for their respective endogenous substrates in vivo, dihydrolanosterol for human CYP51 (V mx = 0.5 nmol/min/nmol CYP51) and 24-methylene-24,25-dihydrolanosterol for C. albicans CYP51 (V mx = 0.3 nmol/min/nmol CYP51). In contrast, S. bicolor CYP51 showed strict substrate specificity and selectivity towards its own endogenous substrate, obtusifoliol (V mx = 5.5 nmol/min/nmol CYP51) and was inactive towards 14K K-demethylation of lanosterol, 24-methylene-24,25-dihydrolanosterol and dihydrolanosterol. These findings confirm that the presence of the 4L L-methyl group in the sterol molecule renders the plant CYP51 incapable of 14K K-demethylation thus revealing the strict active site conservation of plant CYP51 during evolution.z 1998 Federation of European Biochemical Societies.

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Section: Metabolism Of Obtusifoliolmentioning

confidence: 99%

Molecular diversity of sterol 14α‐demethylase substrates in plants, fungi and humans

Lamb

Kelly

1998

FEBS Letters

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“…Phylogenetically, mimivirus and other giant viruses are very old and are thought to have existed prior to cellular organisms (9). Furthermore, it was previously proposed that a form of cytochrome P450 has been present in life forms for billions of years and before the advent of free atmospheric oxygen (10). Subsequently P450 had protective value in detoxifying reactive oxygen species and was retained in aerobic or- on May 10, 2018 by guest http://jvi.asm.org/ hosts for mimivirus.…”

mentioning

confidence: 99%

The First Virally Encoded Cytochrome P450

Lamb

Lei²,

Warrilow

et al. 2009

J Virol

127

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The genome sequence of the giant virus Acanthamoeba polyphaga mimivirus revealed the presence of two putative cytochrome P450 (CYP) genes. The product of one of the two predicted CYP genes (YP_143162) showed low-level homology to sterol 14-demethylase (CYP51) and contained a C-terminal polypeptide domain of unknown function. YP_143162 expression (without an N-terminal membrane binding domain) in Escherichia coli yields a CYP protein which gives a reduced CO difference maximum at 448 nm and was formally demonstrated as the first viral cytochrome P450. Analysis of binding of lipid and sterol substrates indicated no perturbation in CYP heme environment, and an absence of activity was seen when 14-methyl sterols were used as a substrate. The function of the CYP protein and its C-terminal domain remain unknown. taxidϭ10239&optϭVirus).Acanthamoeba polyphaga mimivirus is the largest known virus, which grows in amoeba (5). In 2004, the 1.2-Mbp genome of mimivirus (GenBank accession no. AY653733) was sequenced (9). Its genome is larger than that of several bacteria and archaea and is predicted to encode 911 proteins, among which only 298 have predicted functions. Many atypical proteins are predicted to be encoded by the mimivirus genome, including key protein translation enzymes, a full complement of DNA repair pathway components, and the unique presence of three different topoisomerases (9). Interestingly, among genes never yet reported to occur in a virus, mimivirus contained two putative gene sequences predicted to encode cytochrome P450 enzymes (GenBank accession no. YP_142886 and YP_143162, also known as MIMI_L532 and MIMI_L808, respectively). First, YP_142886 is a putative protein of 468 amino acids in length. In a BLASTP search, this putative CYP protein showed homology to a range of bacterial P450 proteins, including a P450 protein from Chloroflexus aurantiacus (23% identity) and CYP171 from Streptomyces peucetius (23% identity). Additionally, YP_142886 also showed homology at the same level to nematode P450 proteins, including Caenorhabditis briggsae CYP37B1 (25% identity) and a P450 protein from the sea squirt Ciona intestinalis similar to the CYP4 family (24% identity). Efforts in our laboratory to express the YP_142886 gene and verify that it indeed encodes a cytochrome P450 have been unsuccessful, but additional attempts are in progress. The mimivirus protein YP_143886 was designated CYP5254A1 by David Nelson (http://drnelson.utmem .edu/CytochromeP450.html).The second putative mimivirus CYP protein (YP_143162) showed in a BLASTP search the strongest homology to CYP51 proteins (7) from a variety of organisms, including protozoal CYP51 proteins from, e.g., Leishmania major (23% identity); plant CYP51 proteins from, e.g., Arabidopsis thaliana (22% identity); and fungal CYP51 proteins from, e.g., Aspergillus fumigatus (21% identity). This homology is low, strongly suggesting the absence of a functional link. Further analysis of the YP_143162 709-amino-acid sequence revealed this putative CYP protein to be appro...

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“…Cytochrome P450 has probably been present in living organisms before the advent of free oxygen and before the development of other respiratory hemeproteins. 65 This view is strengthened by the finding that cytochrome P450 can catalyze the reductive metabolism of a variety of compounds, particularly under anaerobic conditions. As a defence for the anaerobic life forms against oxygen, cytochrome P450 reduced the oxygen toxic at atmospheric cconcentrations.…”

Section: Oxygenmentioning

confidence: 94%

Hormesis in precautionary regulatory culture: models preferences and the advancement of science

Hanekamp¹,

Bast

2007

Hum Exp Toxicol

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The article focuses on flaws in the actual approaches of exposure to a chemical of recipient organisms. It demonstrates the excessive use of arguments based on adverse effects and underlines the necessity to take adaptive effects seriously. Regulators are invited to rethink their inclination to the `When in doubt, keep it out.' precautionary approach, with results in counter-productive and costly regulations. The authors are clear about the necessity to include hormesis, in the form of a toxicological insignificant exposure (TIE) level, related to the concentration, as a regulatory translation of adaptive effects. This inclusion might well be the `brake' for the looming `collision' with reality of the actual linear toxicological models. This analysis includes the advice to EPA, not to follow the `witch hunt of synthetic chemicals' as embodied in the EU REACH program. Human & Experimental Toxicology (2007) 26, 855 — 873

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Early role during chemical evolution for cytochrome P450 in oxygen detoxification

Cited by 49 publications

References 12 publications

Molecular diversity of sterol 14α‐demethylase substrates in plants, fungi and humans

Molecular diversity of sterol 14α‐demethylase substrates in plants, fungi and humans

The First Virally Encoded Cytochrome P450

Hormesis in precautionary regulatory culture: models preferences and the advancement of science

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