The Evolution of Enzyme Specificity in Fasciola spp.

James A. Irving, Terry W. Spithill, Robert N. Pike, James C. Whisstock, Peter M. Smooker

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Fasciola spp., commonly known as liver fluke, are significant trematode parasites of livestock and humans. They secrete several cathepsin L-like cysteine proteases, some of which differ in enzymatic properties and timing of expression in the parasite's life cycle. A detailed sequence and evolutionary analysis is presented, based on 18 cathepsin L-like enzymes isolated from Fasciola spp. (including a novel clone identified in this study). The enzymes form a monophyletic group which has experienced several gene duplication events over the last ~135 million years, giving rise to the present-day enzymatic repertoire of the parasite. This timing of these duplications appears to correlate with important points in the evolution of the mammalian hosts. Furthermore, the dates suggest that Fasciola hepatica and Fasciola gigantica diverged around 19 million years ago. A novel analysis, based on the pattern of amino acid diversity, was used to identify sites in the enzyme that are predicted to be subject to positive adaptive evolution. Many of these sites occur within the active site cleft of the enzymes, and hence would be expected to lead to differences in substrate specificity. Using homology modeling, with reference to previously obtained biochemical data, we are able to predict S2 subsite specificity for these enzymes: specifically those that can accommodate bulky hydrophobic residues in the P2 position and those that cannot. A number of other positions subject to evolutionary pressure and potentially significant for enzyme function are also identified, including sites anticipated to diminish cystatin binding affinity.
Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalJournal of Molecular Evolution
Volume57
Issue number1
DOIs
Publication statusPublished - 2003

Fingerprint

Fasciola
enzyme
Enzymes
enzymes
cathepsin L
Cathepsin L
Fasciola hepatica
parasite
Parasites
parasites
Cystatins
Fasciola gigantica
cystatins
liver flukes
Gene Duplication
Cysteine Proteases
cysteine proteinases
Livestock
gene duplication
substrate specificity

Cite this

Irving, J. A., Spithill, T. W., Pike, R. N., Whisstock, J. C., & Smooker, P. M. (2003). The Evolution of Enzyme Specificity in Fasciola spp. Journal of Molecular Evolution, 57(1), 1-15. https://doi.org/10.1007/s00239-002-2434-x
Irving, James A. ; Spithill, Terry W. ; Pike, Robert N. ; Whisstock, James C. ; Smooker, Peter M. / The Evolution of Enzyme Specificity in Fasciola spp. In: Journal of Molecular Evolution. 2003 ; Vol. 57, No. 1. pp. 1-15.
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Irving, JA, Spithill, TW, Pike, RN, Whisstock, JC & Smooker, PM 2003, 'The Evolution of Enzyme Specificity in Fasciola spp.', Journal of Molecular Evolution, vol. 57, no. 1, pp. 1-15. https://doi.org/10.1007/s00239-002-2434-x

The Evolution of Enzyme Specificity in Fasciola spp. / Irving, James A.; Spithill, Terry W.; Pike, Robert N.; Whisstock, James C.; Smooker, Peter M.

In: Journal of Molecular Evolution, Vol. 57, No. 1, 2003, p. 1-15.

Research output: Contribution to journalArticle

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T1 - The Evolution of Enzyme Specificity in Fasciola spp.

AU - Irving, James A.

AU - Spithill, Terry W.

AU - Pike, Robert N.

AU - Whisstock, James C.

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N2 - Fasciola spp., commonly known as liver fluke, are significant trematode parasites of livestock and humans. They secrete several cathepsin L-like cysteine proteases, some of which differ in enzymatic properties and timing of expression in the parasite's life cycle. A detailed sequence and evolutionary analysis is presented, based on 18 cathepsin L-like enzymes isolated from Fasciola spp. (including a novel clone identified in this study). The enzymes form a monophyletic group which has experienced several gene duplication events over the last ~135 million years, giving rise to the present-day enzymatic repertoire of the parasite. This timing of these duplications appears to correlate with important points in the evolution of the mammalian hosts. Furthermore, the dates suggest that Fasciola hepatica and Fasciola gigantica diverged around 19 million years ago. A novel analysis, based on the pattern of amino acid diversity, was used to identify sites in the enzyme that are predicted to be subject to positive adaptive evolution. Many of these sites occur within the active site cleft of the enzymes, and hence would be expected to lead to differences in substrate specificity. Using homology modeling, with reference to previously obtained biochemical data, we are able to predict S2 subsite specificity for these enzymes: specifically those that can accommodate bulky hydrophobic residues in the P2 position and those that cannot. A number of other positions subject to evolutionary pressure and potentially significant for enzyme function are also identified, including sites anticipated to diminish cystatin binding affinity.

AB - Fasciola spp., commonly known as liver fluke, are significant trematode parasites of livestock and humans. They secrete several cathepsin L-like cysteine proteases, some of which differ in enzymatic properties and timing of expression in the parasite's life cycle. A detailed sequence and evolutionary analysis is presented, based on 18 cathepsin L-like enzymes isolated from Fasciola spp. (including a novel clone identified in this study). The enzymes form a monophyletic group which has experienced several gene duplication events over the last ~135 million years, giving rise to the present-day enzymatic repertoire of the parasite. This timing of these duplications appears to correlate with important points in the evolution of the mammalian hosts. Furthermore, the dates suggest that Fasciola hepatica and Fasciola gigantica diverged around 19 million years ago. A novel analysis, based on the pattern of amino acid diversity, was used to identify sites in the enzyme that are predicted to be subject to positive adaptive evolution. Many of these sites occur within the active site cleft of the enzymes, and hence would be expected to lead to differences in substrate specificity. Using homology modeling, with reference to previously obtained biochemical data, we are able to predict S2 subsite specificity for these enzymes: specifically those that can accommodate bulky hydrophobic residues in the P2 position and those that cannot. A number of other positions subject to evolutionary pressure and potentially significant for enzyme function are also identified, including sites anticipated to diminish cystatin binding affinity.

KW - Adaptive evolution

KW - Cathepsin L

KW - Enzyme specificity

KW - Fasciola spp

KW - Molecular clock

KW - Phylogeny

KW - Sequence analysis

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DO - 10.1007/s00239-002-2434-x

M3 - Article

VL - 57

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EP - 15

JO - Journal of Molecular Evolution

JF - Journal of Molecular Evolution

SN - 0022-2844

IS - 1

ER -