Metazoan cytochrome P450 evolution

doi:10.1016/S0742-8413(98)10027-0

Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology

Volume 121, Issues 1–3, 1 November 1998, Pages 15-22

https://doi.org/10.1016/S0742-8413(98)10027-0 Get rights and content

Abstract

There are 37 cytochrome P450 families currently identified in animals. The concept of higher order groupings of P450 families called P450 CLANS is introduced. The mammalian CYP3 and CYP5 families belong to the same clan as insect CYP6 and CYP9. All mitochondrial P450s seem to belong to the same clan. Lack of mitochondrial P450s in C. elegans suggests that mitochondrial P450s probably arose from the mistargeting of a microsomal P450 after the coelomates diverged from acoelomates and pseudocoelomates. Different taxonomic groups appear to have recruited different ancestral P450s for expansion as they evolved, since each major taxon seems to have one large cluster of P450s. In insects, this cluster derives from the ancestor to the CYP4 family. Vertebrates and C. elegans may have used the same ancestor independently to generate the CYP1, 2, 17, and 21 families in vertebrates and a large distinctive clan with 45 genes in C. elegans.

Introduction

There has been considerable growth in the number of cytochrome P450 sequences obtained from plants, animals, lower eukaryotes and bacteria in the last few years. In fact, the nomenclature system devised over 10 years ago [6]is now choked with families and soon the two-digit CYP names will all be assigned. This should not be a problem, since three-digit CYP names will surely suffice for many years. This volume of Comparative Biochemistry and Physiology focuses on animal P450s, so it is fitting to provide an overview of animal P450 evolution, as seen from a wider perspective. Individual animal phyla, subphyla, superclasses and classes will be dealt with in more specialized articles.

Lynn Margulis and Karlene Schwartz, in their book Five Kingdoms [5], recognize 32 animal phyla. We, as humans, tend to think mainly of vertebrates, but that is just one subgroup of the Chordata, which is just one of the 32 phyla of animals. This volume on animal cytochrome P450s has seven phyla represented, Cnidaria (sea anemone), Nematoda (C. elegans), Mollusca, Annelida, Arthropoda (insects, crustaceans) Echinodermata and Chordata (fish, birds, amphibians, reptiles and mammals). This leaves us guessing about the 25 other phyla, but this volume really represents the beginning of a story that will no doubt be epic in nature.

Even with a partial glimpse of animal P450s, much can be learned about the history of this class of proteins. It is instructive to look for the presence or absence of families of P450s in the different groups of organisms to estimate if the families are ancient or modern. Which P450s were present in the ancestors of modern animals, and what do these P450s do? What makes them so useful to a wide variety of creatures? The nomenclature of cytochrome P450s has been published [7], and more recent additions to the collection are maintained at a P450 web site at http://drnelson.utmem.edu/nelsonhomepage.html.

Section snippets

Distribution of P450 families in animals

There are currently 37 cytochrome P450 families identified in the animals. Of these only 16 are found in mammals. The other 21 families are exclusively from insects (six families), molluscs (two families) and the nematode C. elegans (13 families). The 16 families found in mammals are not exclusively mammalian. Table 1 summarizes the distribution of animal P450 families in the various taxa. Many of the mammalian families are also found in birds, fish and other vertebrates. Families 1, 2, 3, 4,

Differences in P450s between major taxonomic groups

The discussion here has emphasized the similarities across taxa. Much can also be learned from the differences between organisms. The C. elegans genome is now 67% complete, so nearly all the P450 families in C. elegans should be present in the sequence databases 3, 9. A comparison of mammals with C. elegans reveals some striking absences. Most notably, the steroidogenic and mitochondrial P450s seem absent in C. elegans. Blast searches of the C. elegans genome database identified 70 P450

The origin of mitochondrial P450s from a microsomal P450

One surprising result of this analysis is the conclusion that mitochondrial P450s did not arrive as part of the ancestral mitochondrial endosymbiont. If mitochondrial P450s did come with the endosymbiont, one would expect to see mitochondrial P450s in nematodes and lower eukaryotes. There are only three P450s in the yeast genome and none are mitochondrial. There do not seem to be any mitochondrial P450s in C. elegans. This implies that mitochondria picked up P450s from outside, presumably by

Recruitment of P450s for expansion in different taxa

The C. elegans P450 complement has three fairly large families, CYP13 (14 members), CYP33 (17 members) and CYP35 (nine members). The CYP13 family belongs to the CYP3 CLAN, but CYP33 and CYP35 cluster together at the top of the tree with CYP1, 2, 18, 17 and 21. During animal development, we have seen the expansion of the CYP2 family in mammals and presumably in other vertebrates, the CYP4 family in insects and now the expansion of CYP3 and another cluster called the C. elegans CLAN, that

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Cytochrome P450 monooxygenases play an important role in the biosynthesis and detoxification of endogenous compounds. In this study, we analyzed a number of P450 genes through transcriptome-wide and genome analyses in Aphis gossypii Glover, the most notorious cotton pests. A total of 49 CYP-putative sequences were identified and classified into 13 families and 21 subfamilies. We identified a putative P450 motif (FXXGXXXCXG), and further analyzed other conserved sequences, which indicate that forty-seven of the forty-nine genes seem to be functional, but one is likely non-functional and one is predicted pseudogenes. We found that P450-encoding genes are conserved in gene structure and organization (number, position, and phase of introns) in cotton aphids. The size, transcription orientation, and comparison with other insects of the cotton aphid P450 family suggested that it has evolutionary differentiation. The distribution across the genome and phylogenetic clustering analysis indicated past occurrence of gene duplication events. These results may provide valuable clues for understanding the evolution of the aphid genome, studying the functions of P450s in cotton aphid, and further selecting candidate genes for novel insect control methods.
Characterization, expression and functional analysis of CYP306a1 in the oriental river prawn, Macrobrachium nipponense
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The CYP306a1 gene is a member of the Halloween genes in the cytochrome P450 supergene family, which play an important regulatory role in the synthesis of 20-hydroxyecdysone (20E) in arthropods. In this study, we cloned the full-length DNA sequence of the CYP306a1 (Mn-CYP306a1) gene in the oriental river prawn Macrobrachium nipponense. The sequence encoded 600 amino acids, including typical CYP450 conserved domains. We detected the expression of Mn-CYP306a1 in different tissues of male and female M. nipponense by qRT-PCR. The results showed that the gene was highly expressed in its respective gonadal tissues (ovary and testis). Mn-CYP306a1 was expressed in embryonic and metamorphic developmental stages, and the expression trend appeared in a wave pattern, firstly rising gradually, with peaks appearing in the L1 gastrulation stage and later at the PL10 and PL25 metamorphic stages. RNA interference (RNAi) experiments have found that Mn-CYP306a1 dsRNA can effectively reduce the content of 20E and the molting frequency of M. nipponense. The molting frequency of the experimental group was almost half that of the control group. Moreover, the body weight of M. nipponense was also significantly negatively affected in the late stage of the RNAi experiment. This study showed that Mn-CYP306a1 played an important role in promoting 20E synthesis in M. nipponense.
Comparative analysis of the detoxification gene inventory of four major Spodoptera pest species in response to xenobiotics
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The genus Spodoptera (Lepidoptera: Noctuidae) comprises some of the most polyphagous and destructive agricultural pests worldwide. The success of many species of this genus is due to their striking abilities to adapt to a broad range of host plants. Superfamilies of detoxification genes play a crucial role in the adaption to overcome plant defense mechanisms mediated by numerous secondary metabolites and toxins. Over the past decade, a substantial amount of expression data in Spodoptera larvae was produced for those genes in response to xenobiotics such as plant secondary metabolites, but also insecticide exposure. However, this information is scattered throughout the literature and in most cases does not allow to clearly identify candidate genes involved in host-plant adaptation and insecticide resistance. In the present review, we analyzed and compiled information on close to 600 pairs of inducers (xenobiotics) and induced genes from four main Spodoptera species: S. exigua, S. frugiperda, S. littoralis and S. litura. The cytochrome P450 monooxygenases (P450s; encoded by CYP genes) were the most upregulated detoxification genes across the literature for all four species. Most of the data was provided from studies on S. litura, followed by S. exigua, S. frugiperda and S. littoralis. We examined whether these detoxification genes were reported for larval survival under xenobiotic challenge in forward and reverse genetic studies. We further analyzed whether biochemical assays were carried out showing the ability of corresponding enzymes and transporters to breakdown and excrete xenobiotics, respectively. This revealed a clear disparity between species and the lack of genetic and biochemical information in S. frugiperda. Finally, we discussed the biological importance of detoxification genes for this genus and propose a workflow to study the involvement of these enzymes in an ecological and agricultural context.
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Citation Excerpt :
This process is well understood and divided into three phases. 'Phase I involves the chemical rearrangement by Cytochrome P450, which leads to improved hydrophilicity which faciltates elimination or unmasks vulnerable groups which may be processed by Phase II enzymes (Nelson, 1998). Phase II involves, among other reactions, the conjugation of glutathione (GSH) to electrophilic compounds, like thioether linkages (Hayes et al., 2005), by Glutathione-S-transferase enzymes (GST).
The concern about pharmaceuticals has been increased over the last decade due to their burgeoning consumption. Ibuprofen has an extensive presence in surface water with risks for the aquatic biota. This study focuses on the effects of ibuprofen at environmental concentrations on the survival, transcriptional level, and enzymatic activity for 24, 96 h on Chironomus riparius. Ibuprofen developed a substantial effect on survival by all the conditions. mRNA levels of EcR, Dronc, and Met (endocrine system), hsp70, hsp24, and hsp27 (stress response), and Proph and Def (immune system) were modified, joined to increased GST and PO activity. The results confirmed alterations on the development of C. riparius, as well as two essential mechanisms, involved in protection against external toxicological challenge. Ibuprofen poses an incipient risk to C. riparius and could at an organismal level by compromising their survival, development, and ability to respond to adverse conditions on the future populations.
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The P450 family (CYP genes) of arthropods encodes diverse enzymes involved in the metabolism of foreign compounds and in essential endocrine or ecophysiological functions. The P450 sequences (CYPome) from 40 arthropod species were manually curated, including 31 complete CYPomes, and a maximum likelihood phylogeny of nearly 3000 sequences is presented. Arthropod CYPomes are assembled from members of six CYP clans of variable size, the CYP2, CYP3, CYP4 and mitochondrial clans, as well as the CYP20 and CYP16 clans that are not found in Neoptera. CYPome sizes vary from two dozen genes in some parasitic species to over 200 in species as diverse as collembolans or ticks. CYPomes are comprised of few CYP families with many genes and many CYP families with few genes, and this distribution is the result of dynamic birth and death processes. Lineage-specific expansions or blooms are found throughout the phylogeny and often result in genomic clusters that appear to form a reservoir of catalytic diversity maintained as heritable units. Among the many P450s with physiological functions, six CYP families are involved in ecdysteroid metabolism. However, five so-called Halloween genes are not universally represented and do not constitute the unique pathway of ecdysteroid biosynthesis. The diversity of arthropod CYPomes has only partially been uncovered to date and many P450s with physiological functions regulating the synthesis and degradation of endogenous signal molecules (including ecdysteroids) and semiochemicals (including pheromones and defense chemicals) remain to be discovered. Sequence diversity of arthropod P450s is extreme, and P450 sequences lacking the universally conserved Cys ligand to the heme have evolved several times. A better understanding of P450 evolution is needed to discern the relative contributions of stochastic processes and adaptive processes in shaping the size and diversity of CYPomes.

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¹: This article was invited by Guest Editors Dr John J. Stegeman and Dr David R. Livingstone to be part of a special issue of CBP on Cytochrome P450 (Comp. Biochem. Physiol. 121 C, pages 1–412, 1998).

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Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology

Abstract

Introduction

Section snippets

Distribution of P450 families in animals

Differences in P450s between major taxonomic groups

The origin of mitochondrial P450s from a microsomal P450

Recruitment of P450s for expansion in different taxa

References (9)

A gene encoding a yeast equivalent of mammalian NADPH-adrenodoxin oxidoreductases

Gene

Sterol structure and membrane function

CRC Crit Rev Biochem

Redundant genome sequencing?

Science

The nematode Caenorhabditis elegans and its genome

Science

Cited by (176)

Characterization of P450 monooxygenase gene family in the cotton aphid, Aphis gossypii Glover

Characterization, expression and functional analysis of CYP306a1 in the oriental river prawn, Macrobrachium nipponense

Comparative analysis of the detoxification gene inventory of four major Spodoptera pest species in response to xenobiotics

In silico modeling and molecular docking insights of kaempferitrin for colon cancer-related molecular targets

Ibuprofen as an emerging pollutant on non-target aquatic invertebrates: Effects on Chironomus riparius

Diversity and evolution of the P450 family in arthropods

ReviewMetazoan cytochrome P450 evolution1

Abstract

Introduction

Section snippets

Distribution of P450 families in animals

Differences in P450s between major taxonomic groups

The origin of mitochondrial P450s from a microsomal P450

Recruitment of P450s for expansion in different taxa

Gene

Sterol structure and membrane function

CRC Crit Rev Biochem

Redundant genome sequencing?

Science

The nematode Caenorhabditis elegans and its genome

Science

Review
Metazoan cytochrome P450 evolution¹