*Department of Medical Microbiology, University of Georgia;
and
Department of Biological Sciences, University of Nevada at Las Vegas
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Abstract |
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Introduction |
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The classification scheme of glycoside hydrolases provides an archetype example of the hierarchical relationships among a widespread evolutionarily and/or functionally related superfamily of enzymes (Henrissat 1991, 1998
; Henrissat and Bairoch 1993, 1996
; Henrissat and Romeu 1995
; Henrissat and Davies 1997
). Glycoside hydrolases are enzymes that hydrolyze the glycosidic bond between carbohydrates or between a carbohydrate and a noncarbohydrate moiety. The innovative sequence-based classification system originally proposed by Henrissat (1991)
currently consists of 66 families of glycoside hydrolases (see http://expasy.hcuge.ch/cgi-bin/lists?glycosid.txt). Structural and functional characteristics that indicate relationships between members of different families have resulted in the designation of clans that are composed of two or more families.
-Mannosidases are glycoside hydrolases involved in both the maturation and the degradation of Asn-linked oligosaccharides (Dewald and Touster 1973
; Tulsiani et al. 1982
; Lal et al. 1994
; Liao, Lal, and Moremen 1996
). The glycoprotein maturation and degradation pathways are very conserved, and
-mannosidase activities have been detected in all eukaryotes assayed.
-Mannosidaseencoding genes have been isolated and their products characterized from a diverse group of eukaryotes, including the protozoan Trypanosoma cruzi, the yeast Saccharomyces cerevisiae, and the metazoans Drosophila melanogaster and Homo sapiens (Camirand et al. 1991
; Kerscher et al. 1995
; Liao, Lal, and Moremen 1996
; Vandersall-Nairn et al. 1998
). Traditionally,
-mannosidases have been organized into two classes (I and II) based on both functional characteristics and sequence homology (Moremen, Trimble, and Herscovics 1994
; Henrissat 1998
). The cellular compartment where they catalyze mannose hydrolysis (e.g., endoplasmic reticulum, Golgi, or lysosome) further distinguishes different
-mannosidase enzymes.
Class I -mannosidase enzymes thus far characterized are all involved in the maturation of Asn-linked oligosaccharides. These enzymes all process the trimming of Man9GlcNAc2 to Man5GlcNAc2. While class I
-mannosidase enzymes only hydrolyze
-1,2 mannose bonds, they differ in their stereospecificities (Lal et al. 1994
). Class I
-mannosidase enzymes are localized to either the endoplasmic reticulum or the Golgi complex. The majority of class II
-mannosidase enzymes that have been characterized catalyze the degradation of Asn-linked oligosaccharides. Class II
-mannosidase enzymes show less biochemical specificity, as they possess
-1,3,
-1,6, and
-1,2 hydrolytic activity. Enzymes of this class also have a wider range of cellular compartmentalization and can be localized to the cytosol and lysosomes in addition to the Golgi complex.
The rapid accumulation of genomic and cDNA nucleotide sequences in the various public databases has facilitated the in silico discovery of several putative -mannosidase sequences with statistically significant similarities to classically cloned and functionally characterized
-mannosidase genes. Using a diverse representative set of
-mannosidase amino acid query sequences, an exhaustive search for and analysis of
-mannosidase homologous sequences was performed. Sequence retrieval, alignment, and phylogenetic analysis allowed a determination of the range and extent of
-mannosidase variation. The relationship among previously characterized and novel putative
-mannosidase sequences is defined and a classification consistent with the Henrissat scheme is proposed. The comparative method was used to assess the correlation between phylogenetic relationship and cellular localization of biochemically characterized
-mannosidase sequences. Finally, the existence of closely related orthologs and paralogs in the
-mannosidase IA-IB clade allowed a test for positive Darwinian selection for altered function following gene duplication.
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Materials and Methods |
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The sequences analyzed here correspond to the GenBank accession numbers listed below. The accessions include both nucleotide and amino acid sequences. The sequence abbreviations and their corresponding accession numbers follow the species names. Sequence abbreviations consist of two letters that represent the species binomial followed by a single-letter designation that indicates the cellular location of activity for functionally characterized sequences or a "p" to indicate putative -mannosidase sequences that have not yet been biochemically characterized. Cellular compartmentalization abbreviations are as follows: E, endoplasmic reticulum; M, membrane-associated; G, Golgi apparatus; L, lysosome; X, extracellular; and V, vacuolar. Roman numerals that indicate the identity of the
-mannosidase family to which a sequence belongs make up the final component of the sequence abbreviations. The accession number list is as follows: Arabidopsis thalianaAT-LII, Y11767; Aspergillus saitoiAS-XI, D49827; Bos taurusBT-LII, L31373; Caenorhabditis elegansCE-pI.1, Z78012; CE-pI.2, Z73906; CE-pI.5, Z81497; CE-pI.7, Z68882; CE-pII.1, U40948; CE-pI.3, Z68270; CE-pI.6, Z47073; CE-pI.4, U41272; CE-pII.3, U97015; CE-pII.2, Z75954; Dictyostelium discoideumDD-LII, M82822; Drosophila melanogasterDM-GI, X82641; DM-pI, AL021086; DM-GII.1, X77652; DM-GII.2, AB018079; Escherichia coliEC-pIII, AE000176; Emericella nidulansEN-pIII, AF016850; Felis catusFC-LII, AF010191; Homo sapiensHS-EIII, AF044414; HS-LII, U68567; HS-GII.1, U31520; HS-GII.2, D55649; HS-pI, D86967; HS-GIA, X74837; HS-GIB, AF027156; Mus musculusMM-MII, AB006458; MM-GIA, U04299; MM-LII, U87240; MM-GIB, AF078095; MM-GII, X61172; Mycobacterium tuberculosisMT-pIII, Z92772; Oryctolagus cuniculusOC-GIA, U04301; Penicillium citrinumPC-XI, D45839; Pyrococcus horikoshiiPH-pIII, AP000003; Rattus norvegicusRN-EIII, M57547; RN-GII, M24353; Saccharomyces cerevisiaeSC-EI, Z49631; SC-VIII, M29146; SC-pI.1, U00030; SC-pI.2, Z73229; Schizosaccharomyces pombeSP-pI, AL021813; Spodoptera frugiperdaSF-GI, AF005035; SF-GII, AF005034; Sus scrofaSS-MII, D28521; SS-GIA, Y12503; SynechocystisSY-pIII, D63999; Trypanosma cruziTC-LII, AF077741.
Sequence Alignment
The CLUSTAL W (Thompson, Higgins, and Gibson 1994
) and PROBE (Neuwald et al. 1997
) programs were used to align amino acid sequences. Initial alignments of the total data set performed with CLUSTAL W revealed a highly divergent group of sequences, and therefore CLUSTAL W was not able to obtain an optimal global alignment. To effectively align the total amino acid data set, the PROBE program was used to identify a common ordered series of motifs (OSM) among all sequences. An alignment of diagnostic sites was extracted from the total OSM alignment. Diagnositic sites were chosen from sites that a PAUP* 4.0b parsimony reconstruction classified as apomorphies with a consistency index of 1 and that supported internal branches leading to the three main clades (families). Higher levels of amino acid sequence identity within families allowed the use of CLUSTAL W for within-family multiple alignments. CLUSTAL W was run with the PAM250 distance matrix and default gap penalty options. The relatively high sequence identity and the use of CLUSTAL W for within-family multiple alignment allowed for the inclusion of motif intervening regions (MIRs). MIRs contain additional information necessary to obtain accurate within-family phylogenetic reconstructions (McClure and Kowalski 1999
).
Phylogenetic Analysis
Within-family and among-families amino acid alignments were used with the PAUP* 4.0b package (Swofford 1998
) to reconstruct the phylogenies reported here. Both parsimony and the neighbor-joining (Saitou and Nei 1987
) distance method were used in phylogenetic reconstruction. Parsimony heuristic searches were conducted with 10 replicates of random stepwise addition and tree bisection reconnection. Distance-based and parsimony methods gave virtually identical results. All topologies reported here are based on the neighbor-joining method. Trees were rooted with midpoint rooting along the longest branch. One hundred bootstrap replicates were performed using the full heuristic bootstrap option.
Amino Acid Sequence Diversity
Average percentages of amino acid identity and standard deviations within and between families were calculated using a subset of 12 sequences (four representatives from each family). The PAUP* 4.0b program was used to calculate the mean character difference distance matrix. Mean character differences were converted to percentages of identity and averaged within and between the three families.
Nucleotide Sequence Diversity
Closely related amino acid sequences for the Golgi -mannosidase IA-IB clade were aligned using CLUSTAL W with the default options. The Golgi
-mannosidase IA-IB phylogeny was reconstructed as described above. Nucleotide sequences of the same taxa were aligned to correspond to the amino acid alignment using the DNA Stacks program (Eernisse 1992
). Ancestral nucleotide sequences were inferred with parsimony using PAUP* 4.0b. The DnaSP program (Rozas and Rozas 1997
) was used to calculate Ka and Ks values according to the method of Nei and Gojobori (1986)
and to perform the McDonald-Kreitman test of neutrality (McDonald and Kreitman 1991
). The time elapsed since IA-IB duplication (TD) was calculated with Ks values using the method of Li (1997)
. This calculation was calibrated using the time elapsed since human-mouse speciation (TS) (Kumar and Hedges 1998
).
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Results and Discussion |
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Phylogeny and Classification
The OSM alignment was used to reconstruct a global -mannosidase phylogeny (fig. 1
). The resulting neighbor-joining tree reveals three robust clades of
-mannosidase sequences. A parsimony phylogeny reconstructed using the OSM alignment showed an identical topology with the exception of a few weakly supported branches within the three main clades. Distance-based and parsimony phylogenetic reconstructions based on the suboptimal CLUSTAL W alignment also gave qualitatively similar results, with the same three major clades and topological differences in weakly supported terminal nodes. Figure 2
shows an alignment of diagnostic sites that clearly distinguish the three major
-mannosidase clades. Average percentages of amino acid identity within and between families (table 1
) are also consistent with the existence of three distinct
-mannosidase clades.
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Clade II is made up of a more diverse set of eukaryotic sequences. In addition to fungal and metazoan isolated sequences, there are also plant, slime mold, and protazoan representatives. Clade II also has the lowest average level of sequence identity (table 1 ). The taxonomic and sequence diversity that characterizes this clade is consistent with the varied biochemical specificities of its taxa. Among the functionally characterized members of this clade, there are sequences with lysosomal, membrane-associated, and Golgi activity. Clade II Golgi -mannosidase enzymes show
-1,3 and
-1,6 mannose bond cleavage distinct from the
-1,2 mannosidase activity of clade I Golgi sequences (Moremen, Trimble, and Herscovics 1994
). Clade II sequences have previously been placed into glycoside hydrolase family 38 (Henrissat 1991
; Henrissat and Bairoch 1993
).
In the unrooted global -mannosidase tree, clade III falls approximately at the midpoint between clades I and II (fig. 3
). This group represents the most diverse taxonomic assemblage of
-mannosidase homologous sequences. Seven of the nine clade III members form a well-supported monophyletic group (fig. 1
). Among these seven sequences, there are metazoan, fungal, and archaean representatives. The two most basal members of this clade are sequences from gram-negative (E. coli) and gram-positive (M. tuberculosis) eubacteria. However, there is no significant bootstrap support for the branches that group these sequences with the other clade III members (fig. 1
). These sequences branch off the most internal node in the global phylogeny (fig. 3
). The phylogenetic location and the eubacterial origin of these sequences suggest that they may be ancestral proto-
-mannosidase enzymes. The fact that these putative ancestral sequences group most closely with clade III is consistent with the diversity of taxa in this clade and suggests that clade III represents the most ancestral
-mannosidase family.
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Above the level of family, the Henrissat scheme includes the designation of clan to cover separate but related families (see http://afmb.cnrs-mrs.fr/~pedro/CAZY/ghf_intro.html). Levels of average percentages of amino acid identity within families (table 1
) indicate that each family represents a distinct homologous group of sequences. Average percentages of amino acid identity between families (table 1
), on the other hand, are very low. Such low identity values suggest that sequences between families cannot be considered homologous with statistical confidence (Dayhoff, Schwartz, and Orcutt 1978
). However, several other criteria suggest the possibility that the three
-mannosidase families studied here share a common ancestor. For example, lineage-specific BLAST searches that use
-mannosidase sequences from one family as a query can detect
-mannosidase sequences from different families. In addition, the presence of the OSM signature is suggestive of homology between families. Thus, while the BLAST results and the OSM signature are suggestive of common ancestry but not definitive, the three families of
-mannosidase sequences reported here are proposed to make up a
-mannosidase clan, or superfamily, based on the combination of this sequence evidence and the functional analogy of the
-mannosidase enzymes.
Gene Duplication and Functional Diversification
Gene duplication is a critical step in generating the functional diversification necessary for the evolution of complex organisms (Ohta 1991
). According to the generally accepted view of gene duplication and evolution, the redundancy created by duplication allows paralogous gene copies to evolve new functions (Ohno 1970
). However, once a paralog acquires a newly evolved function that enhances the fitness of its host, this function is likely to be constrained by negative selection (Goodman, Moore, and Matsuda 1975
). One prediction of this hypothesis is that among the members of a gene family, orthologous copies are likely to encode the same functions, while paralogs will encode diverse functions. The
-mannosidase superfamily, with its abundance of functionally characterized sequences, provides an ideal system to test this prediction. Paralogous
-mannosidase sequences are known to encode slightly different biochemical activities. For example, among clade I, some sequences are ER-specific and some are Golgi-specific. If these discrete compartmentalized activities have evolved subsequent to duplication in the manner proposed above, then they should appear monophyletic when mapped onto a phylogeny of the sequences that encode them.
Within-family (clade I and II) -mannosidase phylogenies were used to test this prediction. Relatively high levels of amino acid sequence homology within families allowed the alignment of MIRs in addition to the OSM. The inclusion of MIRs increased the phylogenetic resolution within families. Within-family phylogenies based on both OSM and MIR sequences showed topologies that were virtually identical (fig. 4
) to the global
-mannosidase tree (fig. 1
) based solely on the OSM alignment. The placement of only one sequence within each tree differed between the within-family and the among-families phylogenies. These results indicate that the OSM likely records an accurate phylogenetic history of the
-mannosidase superfamily despite the fact that it includes only a subset of the total sequence data. The increased resolution afforded by the inclusion of the MIR sequences manifested itself in a general increase in bootstrap support for the within-family trees. In both family I and family II,
-mannosidase sequences that encode enzymes with the same cellular compartmentalization group together in well-supported clades (fig. 4
). These data support the hypothesis of gene duplication followed by functional diversification of paralogs and subsequent canalization of activity among orthologs. The presence of putative sequences in these clades suggests that these as yet uncharacterized sequences will prove to have the same cellular compartmentalization patterns as their close relatives.
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Relative rates of Ka and Ks can yield improtant clues as to the nature of selection acting to shape nucleotide variation. A higher rate of Ka than Ks (Ka/Ks > 1) is generally considered unequivocal evidence of positive Darwinian selection (Kimura 1983
; Hughes and Nei 1988
; Sharp 1997
). Levels of Ka and Ks for the IA- IB clade were analyzed to evaluate the role of selection following gene duplication (table 2
). Comparison of extant IA-IB sequences shows an average Ka/Ks < 1. Such a pattern of variation demonstrates the prevalence of negative selection due to functional constraint on IA and IB amino acid sequences. This result is consistent with the expectations of the neutral theory (Kimura 1983
) and is not surprising when the overall conservation and functional importance of
-mannosidase activity is considered.
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Conclusions |
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Footnotes |
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1 Abbreviations: ER, endoplasmic reticulum; MIR, motif intervening region; OSM, ordered series of motifs.
2 Keywords: -mannosidase
glycoside hydrolase
gene duplication
positive selection
adaptation
1 Present address: Department of Microbiology and Center for Computational Biology, Montana State University.
4 Address for correspondence and reprints: I. King Jordan, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bldg. 38A, Bethesda, MD 20894. E-mail: ikingjordan{at}hotmail.com
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