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==Reconstructed enzymes==
==Reconstructed enzymes==
First proposed in 1963 by Linus Pauling and Emile Zuckerkandl, ancestral reconstruction is the inference and synthesis of a gene from the ancestral form of a group of genes,<ref>Pauling, L. and E. Zuckerkandl, Chemical Paleogenetics Molecular Restoration Studies of Extinct Forms of Life. Acta Chemica Scandinavica, 1963. 17: p. 9-&.</ref> which has had a recent revival thanks to improved inference techniques<ref>{{cite pmid|16789817}}</ref> and low-cost artificial gene synthesis,<ref>{{cite pmid|7590320}}</ref> resulting in several ancestral enzymes —dubbed “stemzymes” by some<ref name=serine>{{cite pmid|14536074}}</ref>—to be studied.<ref>{{cite pmid|15143319}}</ref>



In light of the large number of paralogous fungal α-glucosidase genes with a number of specific maltose-like (maltose, turanose, maltotriose, maltulose and sucrose) and isomaltose-like (isomaltose and palatinose) substrates, a study reconstructed all key ancestors and found that the last common ancestor of the paralogues was mainly active on maltose-like substrates with only trace activity for isomaltose-like sugars, despite leading to a lineage of iso-maltose glucosidases and a lineage that further split into maltose glucosidases and iso-maltose glucosidases. Antithetically, the ancestor before the latter split had a more pronounced isomaltose-like glucosidase activity.<ref name=reconstructed/>
In light of the large number of paralogous fungal α-glucosidase genes with a number of specific maltose-like (maltose, turanose, maltotriose, maltulose and sucrose) and isomaltose-like (isomaltose and palatinose) substrates, a study reconstructed all key ancestors and found that the last common ancestor of the paralogues was mainly active on maltose-like substrates with only trace activity for isomaltose-like sugars, despite leading to a lineage of iso-maltose glucosidases and a lineage that further split into maltose glucosidases and iso-maltose glucosidases. Antithetically, the ancestor before the latter split had a more pronounced isomaltose-like glucosidase activity.<ref name=reconstructed/>


Revision as of 04:26, 28 December 2012

Enzyme promiscuity is a property most enzymes possess which is essential for the evolution of new enzymatic functions. Enzymes are remarkably specific catalysts, but often do possess other activities that are very small and are under neutral selection, called promiscuous activities. Despite being ordinarily irrelevant physiologically, under new selective pressures these activities may confer a fitness benefit therefore prompting the evolution of the formerly promiscuous activity to become the new main activity.[1] An example of this is the atrazine chlorohydrolase (atzA encoded) from Pseudomonas sp. ADP which evolved from melamine deaminase (triA encoded), which has very small promiscuous activity towards atrazine, a man-made chemical.[2]

Introduction

Enzymes are evolved to catalyse a particular reaction on a particular substrate with a high catalytic efficiency (kcat/KM, cf. Michaelis–Menten kinetics). However, in addition to this main activity, they posses other activities that are generally several order of magnitude lower, and that are not a result of evolutionary selection and therefore do not partake in the physiology of the organism.[nb 1] This phenomenon allows new functions to be gained as the promiscuous activity could confer a fitness benefit under a new selective pressure leading to its duplication and selection as a new main activity.

Duplication and divergence

Several theoretical models exist to predict the order of duplication and specialisation events, but the actual process is more intertwined and fuzzy (§ Reconstructed enzymes below).[3] On one hand, gene amplification results in an increase in enzyme concentration, and potentially freedom from a restrictive regulation, therefore increasing the reaction rate (v) of the promiscuous activity of the enzyme making its effects more pronounced physiologically ("gene dosage effect").[4] On the other, enzymes may evolve an increased secondary activity with little loss to the primary activity ("robustness") with little adaptive coflict (§ Robustness and plasticity below).[5]

Robustness and plasticity

A study of three distinct hydrolases (human serum paraoxonase (PON1), pseudomonad phosphotriesterase (PTE) and human carbonic anhydrase II (CAII)) has shown the main activity is "rubust" towards change, whereas the promiscuous activities are more "plastic". Specifically, selecting for an activity that is not the main activity, does not initially diminish the main activity (hence its robustness), but greatly affects the non-selected activities (hence their plasticity).[5]

The phosphotriesterase (PTE) from Pseudomonas diminuta was evolved to become an arylesterase (P–O to C–O hydrolase) in eighteen rounds gaining a 109 shift in specificity (ratio of KM), however most of the change occured in the inital rounds, where the unselected vestigial PTE activity was retained and the evolved arylesterase activity grew, while in the latter rounds there was a little trade-off for the loss of the vestigial PTE activity in favour of the arylesterase activity.[6]

This means firstly that a specialist enzyme (monofunctional) when evolved goes through a generalist stage (multifunctional), before becoming a specialist again —presumably after gene duplication according to the IAD model— and secondly that promiscuous activities are more plastic than the main activity.

Distribution

A series of experiments have been conducted to assess the distribution of promiscuous enzyme activities in E. coli. In E. coli 21 out of 104 single-gene knockouts tested (from the Keio collection[7]) could be rescued by overexpressing a noncognate E. coli protein (using a pooled set of plasmids of the ASKA collection[8]). The mechanisms by which the noncognate ORF could rescue the knockout can be grouped into eight categories: isozyme overexpression (homologues), substrate ambiguity, transport ambiguity (scavenging), catalytic promiscuity, metabolic flux maintanence (including overexpression of the large component of a synthase in the absence of the amine transferase subunit), pathway bypass, regulatory effects and unknown mechanisms.[4] Similarly, overexpressing the ORF collection allowed E. coli to gain over an order of magnitude in resistance in 86 out 237 toxic environment.[9]

Reconstructed enzymes

First proposed in 1963 by Linus Pauling and Emile Zuckerkandl, ancestral reconstruction is the inference and synthesis of a gene from the ancestral form of a group of genes,[10] which has had a recent revival thanks to improved inference techniques[11] and low-cost artificial gene synthesis,[12] resulting in several ancestral enzymes —dubbed “stemzymes” by some[13]—to be studied.[14]


In light of the large number of paralogous fungal α-glucosidase genes with a number of specific maltose-like (maltose, turanose, maltotriose, maltulose and sucrose) and isomaltose-like (isomaltose and palatinose) substrates, a study reconstructed all key ancestors and found that the last common ancestor of the paralogues was mainly active on maltose-like substrates with only trace activity for isomaltose-like sugars, despite leading to a lineage of iso-maltose glucosidases and a lineage that further split into maltose glucosidases and iso-maltose glucosidases. Antithetically, the ancestor before the latter split had a more pronounced isomaltose-like glucosidase activity.[3]

Primordial metabolism

Roy Jensen in 1976 theorised that primordial enzymes had to be highly promiscuous in order for metabolic networks to assemble in a patchwork fashion (hence its name, the patchwork model). This primordial catalytic versatility was later lost in favour of highly catalytic specialised orthologous enzymes.[15] As a consequence, many central-metabolic enzymes have structural homologues that diverged before thelast universal common ancestor.[16]

Plant secondary metabolism

Anthocyanins (delphindin pictured) confer plants, particularly their flowers, with a variety of colours to attract pollinators and a typical example of plant secondary metabolite.

Plants produce a large number of secondary metabolites thanks to enzymes that, unlike those involved in primary metabolism, are less catalytically efficient but have a larger mechanistic elasticity (reaction types) and broader specificities. The liberal drift threshold (caused by the low selective pressure due the small population size) allows the fitness gain endowed by one of the products to maintain the other activities even though they may be physiologically useless.[17]

Drugs and promiscuity

Whereas promiscuity is mainly studied in terms of standard enzyme kinetics, drug binding and subsequent reaction is a promiscuous activity as the enzyme catalyses an inactivating reaction towards a novel substrate it did not evolve to catalyse.[5]


See also

Footnotes

  1. ^ Most authors refer to as promiscuous activities the non-evolved activities and not secondary activities that have been evolved.[1] Consequently, glutathione S-transferases (GSTs) and cytochrome P450 enzymes are termed multispecific or broad-specificity enzymes.[1] The ability to catalyse different reactions is often termed catalytic promiscuity or reaction promiscuity, whereas the ability to act upon different substrates is called substrate promiscuity or substrate ambiguity. The term latent has different meanings depending on the author, namely either referring to a promiscuous activity that arises when one or two residues are mutated or simply as a synonym for promiscuous to avoid the latter term. It should be noted that promiscuity here means muddledom, not lechery —the latter is a recently gained meaning of the word.[18]

References

  1. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 20235827, please use {{cite journal}} with |pmid=20235827 instead.
  2. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19201959, please use {{cite journal}} with |pmid=19201959 instead.
  3. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 23239941, please use {{cite journal}} with |pmid=23239941 instead.
  4. ^ a b Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17884825, please use {{cite journal}} with |pmid=17884825 instead.
  5. ^ a b c Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15568024, please use {{cite journal}} with |pmid=15568024 instead.
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/ncomms2246, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/ncomms2246 instead.
  7. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16738554, please use {{cite journal}} with |pmid=16738554 instead.
  8. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16769691, please use {{cite journal}} with |pmid=16769691 instead.
  9. ^ cite doi|10.1073/pnas.1012108108}}
  10. ^ Pauling, L. and E. Zuckerkandl, Chemical Paleogenetics Molecular Restoration Studies of Extinct Forms of Life. Acta Chemica Scandinavica, 1963. 17: p. 9-&.
  11. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16789817, please use {{cite journal}} with |pmid=16789817 instead.
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 7590320, please use {{cite journal}} with |pmid=7590320 instead.
  13. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14536074, please use {{cite journal}} with |pmid=14536074 instead.
  14. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15143319, please use {{cite journal}} with |pmid=15143319 instead.
  15. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 791073, please use {{cite journal}} with |pmid=791073 instead.
  16. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1186/1471-2148-7-S2-S3, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1186/1471-2148-7-S2-S3 instead.
  17. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1126/science.1217411, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1126/science.1217411 instead.
  18. ^ "promiscuity". Oxford English Dictionary (Online ed.). Oxford University Press. (Subscription or participating institution membership required.)
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