Occurrence of Sphingomyelinases D (SmaseD) in
Bacterial, Fungi, and Arachnida groups: an evolutionary
puzzle
PENA, I.A., FLEURY, C., AZEVEDO, V., ORTEGA, J.M.
LAB. BIODADOS, Depto. Bioquímica e Imunologia, ICB, UFMG, Belo Horizonte, MG, Brazil.
Abstract
Sphingomyelin (SM)-specific Phospholipase D or PLD is able to hydrolise sphingomyelins esther bonds
present in eukaryotic cell membranes. Corynebacterium pseudotuberculosis, Corynebacterium ulcerans and
Arcanobacterium haemolyticum are pathogens, and their virulence is associated with the production of PLD
exotoxin. This Sphingomyelinase D (SMaseD) activity is unknown anyelsewhere in the animal kingdom but is
shared with Loxosceles and Sicarius spiders venoms, and this venom component is the responsible for all
the pathological effects, both local and systemic effects, often resulting in local dermonecrotic lesions.
Recent work has proposed that similarity between Loxosceles SmaseD and PLD is consequence of a Lateral
Gene Transfer (LGT), and this enzymes were originated from a common, broadly conserved domain family,
the Glycerophosphoryl Diester Phosphodiesterases (GDPDs). To search for new species that possess this
enzyme activity, we used bioinformatic tools. Searches using PSI-BLAST found similarity in the species
above, and surprisingly, in three Ascomycetes fungi (Coccidioides immitis, Aspergillus oryzae and
Ajellomyces capsulatus), and in a tick (Ixodes scapularis). tBLASTn and PSI-tBLASTn searches in dbEST
database have revealed ESTs from two more fungi species, one from spider and two more from ticks.
Additional searches in WGS Sequences database have found five more Ascomycetes species. All these
sequences have the seven amino acids from the putative active site extremely conserved, and they probably
share the same molecular function. Similarity values between fungi-bacteria (60-64%) are higher than
bacteria-spider (31-33%) and fungi-spider (31-32%), and because of this, Neighbor-Joining trees (with
bootstrap values around 91%) group the bacterial sequences with fungi ones. Thus, we propose that the
origin of this enzyme in these three groups is associated with possible divergent events from GDPD group
evolution, in either bacteria, fungi or arachnids, followed by lateral gene transfer from one lineage to other, or
this puzzle can be an evolutionary convergence event.
Key words: Lateral Gene Transfer, LGT, phospholipase D, PLD,
sphingomyelinase D, SMaseD, SM-
specifc Phospholipase D
Introduction
Bites from Loxosceles spiders (brown or violin spiders) produce severe clinical symptoms, as
dermonecrotic lesions, and ulcerations. The causative factor is a Sphingomyelinase D (SMaseD) that in
contrast to most phospholipases has an unusual specifc substrate, because of the four major phospholipds
present in the eukariotic plasma membranes, only sphingomyelin is cleaved. This enzyme catalyzes the
hydrolysis of Sphingomyelin via an Mg²+ ion dependent catalytic activity, generating ceramide-1-phosphate
and one amino-alcohol (coline). This reaction can induce lysis mechanisms, as the activation of endogenous
metalloproteinase that cleaves glycophorins and facilites the complement-mediated lysis (Tambourgi et al,
2000; Tambourgi et al, 2005).
An enzyme with the same toxic activity is secreted by a few pathogenic bacteria and called
Sphingomyelin-specific phospholipase D or “PLD” (Bernheimer et al, 1985;) In these bacteria, PLD is the
major virulence and penetrance factor (Carne et al, 1978; Dorella et al, 2005; McNamara et al, 1994) This
enzyme was unknown elsewhere in the animal kingdom until now, but searches using BLAST tools have
found many species that have very similar proteins to SmaseD, and it is likely that these enzymes have a
similar molecular function.
This similarity between spider and bacteria enzymes is a very interesting case, because both have
comparable bioactivity, molecular weight and isoelectric focusing point (Bernheimer et al, 1985),enzyme
kinetics and substrate specificities (van Meeteren et al, 2004) and are so distant related organisms. The
origin of this enzyme is also discuted in many works, and they believe that originated from a common,
broadly conserved domain family, the Glycerophospho-diester Phosphodiesterases (GDPDs). Recent work
suggested that similarities between PLD from C. pseudotuberculosis and SMaseD from the Loxosceles
spiders venom can be an example of a lateral gene transfer (Cordes et al, 2006).
Lateral Gene Transfer (LGT) occurs when genes are transferred among distantly organisms in
evolutionary scale. In bacterial world, the acquisition of new genes thought this mechanism is an important
way of adaptation and genome evolution (Lawrence et al, 2002). Through the process of data accumulation
and analysis, researches can infer that this process also occurs in the evolution of eukaryotic genomes.
However, animals and fungi, although seem to be unaffected, have a few exceptions (Andersson et al,
2005).
The present study describes an extraordinary mystery: many fungi and ticks species have proteins
very similar to related bacterial and spider SmaseD. This similarity is described here using bioinformatic
tools. The molecular function of this proteins was unknown until the moment, but through analysis of the
sequences, molecular modelling, presence of great similarity indexes and conserved putative active site and
other important residues, we believe that these may be related to the activity of Sphingomyelinase D activity.
But as fungi, arachnids and bacteria are so distant in evolutionary scale, is this an event of convergence? Or
are there one (or more) lateral gene transfer event? What is the origin of SmasesD? These are very
important and interesting questions for molecular evolution that we discuss in this article.
Materials and Methods
Bla bla bla
Results
Similarity searches:
We started our analysis through searches in proteic level, to find new protein sequences and new
species. In order to verify these possibilities, PSI-BLAST (Position-Specific Iterated- Basic Local Alignment
Search Tool) searches have been performed. This BLAST module uses position-specific scoring matrices
(PSSMs) that are generating in each iteration based in the protein sequences that are selected in the round.
Because this, the PSI-BLAST becomes be more sensitive program to find distant similarities than BLASTp.
The query used in the first analysis was the C. pseudotuberculosis PLD, and in the first iteration
outputs, we found similar PLDs from Corynebacterium ulcerans and Arcanobacterium haemolyticum, whose
homology is already described (McNamara et al, 1995). Additionally, the BLAST was found proteins from two
Pezizomycotina sub-phylum fungi: Coccidioides immitis and Aspergillus oryzae that are very similar to PLD. In
posterior iterations, similarity indexes with SMasesD from spiders Loxosceles and a protein fof a tick, Ixodes
scapularis was found.
The similarity values between fungi and bacteria (60-64%) are higher than bacteria-spider (31-33%) and
fungi-spider (31-32%). The results are showed in Table 1:
Table 1: PSI-BLAST analisys using the C. pseudotuberculosis PLD, A. oryzae
proteins and Loxosceles SMaseD as queries against NCBI "nr" protein database.
subject:
PLD_CORPS
PLD_CORUL
PLD_ARCHA
PLD_CORPS
Q2U8X2_ASPOR
C.
Q1DJDS_COCIM
pseudotuberculosis
Q2UAL9_ASPOR
fifth iteration
SMD2_LOXRE
SMD5_LOXIN
SMD_IXOSC
PLD_CORPS
PLD_CORUL
PLD_ARCHA
Q2U8X2_ASPOR Q2U8X2_ASPOR
A.oryzae
Q1DJDS_COCIM
sixth iteration
Q2UKE8_ASPOR
SMD2_LOXRE
SMD5_LOXIN
SMD_IXOSC
PLD_CORPS
PLD_CORUL
PLD_ARCHA
SMD5_LOXIN
Q2U8X2_ASPOR
L.intermedia
Q1DJDS_COCIM
sixth iteration
Q2UKE8_ASPOR
SMD5_LOXIN
SMD2_LOXRE
SMD_IXOSC
%id ª %similarity
100
100
86
91
64
76
49
63
47
62
47
61
19
31
17
33
17
31
48
62
47
61
45
61
100
100
50
65
40
57
16
31
19
32
18
30
18
33
18
32
18
31
20
30
19
31
20
36
100
100
49
65
40
55
Align. Weight Score (bits)
307
455
307
448
306
429
280
390
284
378
279
367
335
333
338
275
311
200
284
395
284
386
285
381
391
604
284
368
283
350
329
370
321
279
314
222
344
289
344
285
344
262
339
244
321
247
310
253
305
465
304
523
287
351
The found fungi, Aspergillus oryzae and Coccidioides immitis are taxonomically and phylogenetically
related, in accordance to phylogeny based on complete genomes derived from supertree and combined gene
analysis (Fitzpatrick et al, 2006), and both are able to cause diseases in human (as Aspergillosis and
Coccidioidomycosis).
To verify the existence of other similarity cases that can´t be find by searches in proteic level, as not
annotated proteins of genomes, genomes in sequencing or transcripts, we used the tBLASTn. It compares a
sequence of amino acid against a database of translated nucleotides (the 6-frame nucleotide translated
database sequences).
For this, we used as queries the resulting hits from the PSI-BLAST convergence iterations - amino acid
sequences
from
Corynebacterium
pseudotuberculosis,
Corynebacterium
ulcerans,
Arcanobacterium
haemolyticum, Aspergillus oryzae, Coccidioides immitis, Ixodes scapularis and from spiders belonging to the
Loxosceles genus– to find ESTs (Expressed Sequence Tags) from different species those found in the posterior
searches.
We then used the dbEST (a databank of ESTs) and as a results, ESTs from two fungi species:
Coccidioides posadasii and Trichophyton rubrum, the spider Acanthoscurria gomesiana, and in two more ticks,
Rhipicephalus microplus and Rhipicephalus appendiculatus, showing similarity indexes with the query
sequences. The A. gomesiana ESTs were only obtained as a tBLASTn results as PLD queries from the C.
pseudotuberculosis and the C. ulcerans or from Loxosceles spp. There was no hit against the mentioned fungi
species (Coccidioides immitis and Aspergillus oryzae).
The results are showed in table 2:
Table 2: tBlastn analysis using C. pseudotuberculosis PLD, A. oryzae proteins and
Loxosceles SMaseD as queries against dbEST database of Expressed sequence tags
Query
Best hits (ESTs)
Coccidioides posadasii
Trichophyton rubrum
PLD_CORPS
Acanthoscurria gomesiana
Rhipicephalus microplus
Rhipicephalus appendiculatus
Coccidioides posadasii
Trichophyton rubrum
PLD_CORUL
Rhipicephalus microplus
Rhipicephalus appendiculatus
Coccidioides posadasii
Trichophyton rubrum
PLD_ARCHA
Rhipicephalus microplus
Rhipicephalus appendiculatus
Coccidioides posadasii
Q2U8X2_ASPOR
Trichophyton rubrum
Rhipicephalus appendiculatus
Coccidioides posadasii
Trichophyton rubrum
Q1DJDS_COCIM
Rhipicephalus microplus
Rhipicephalus appendiculatus
Acanthoscurria gomesiana
Rhipicephalus appendiculatus
SMD5_LOXIN
Rhipicephalus microplus
Ixodes scapularis
%id %similarity Align. Weight
47%
64%
257
37%
58%
213
25%
37%
211
48%
62%
48
50%
62%
50
48%
64%
257
37%
58%
214
50%
66%
48
36%
52%
73
47%
63%
257
39%
58%
209
50%
68%
48
50%
65%
44
50%
65%
257
42%
57%
202
34%
58%
55
98%
98%
108
37%
58%
214
31%
47%
92
48%
64%
37
52%
67%
204
32%
49%
225
35%
53%
196
41%
60%
122
Score (bits)
234
156
40
50
48
243
154
45
42
234
157
45,2
42,4
221
118
37,4
217
124
38
36
206
122
122
109
C. posadasii and T. rubrum, are phylogenetically related for the other fungi (C. Immitis and A. Oryzae)
(Fitzpatrick et al, 2006). In relation to Taxonomy, they are from Eurotiomycetes class, Pezizomycotina subphylum, and both are pathogens too, and able to cause human diseases. The ticks found in this step are
phylogenetically related to the tick found in the PSI-BLAST, Ixodes scapularis; pertencing to Ixodidae family of
hard ticks.
In order to check the possibility of find more similarities in proteic level, we resorted to check in a
database of genomes in sequencing, the WGS (Whole Genome Shotgun sequences), that might have species
with similar sequences those don´t have related annotated proteins, and don´t have transcripts sequenced, as
ESTs. We used the tBLASTn against this database (WGS) and new genomic entires from species
taxonomically related to fungi previsiously analyzed have found in this step, and the hits against amino acid
sequences showed a score higher than 100 bits. These new species are: Aspergillus flavus, Uncinocarpus
reesii, Ajellomyces capsulatus (Histoplasma capsulatum) Fusarium oxysporum lycopersici and Giberella
moniliformis – all belonging to the Pezizomycotina sub-phylum, as well as other related fungi (namely:
Aspergillus oryzae, Coccidioides immitis, Coccidioides posadasii and Trichophyton rubrum).
These results are showed in Table 3:
Table 3: tBLASTn using C.pseudotuberculosis PLD, A. oryzae proteins and
Loxosceles SMaseD as queries agains the Whole Genome Shotgun Sequences database
of genomes in sequencing.
Query
Best hits (ESTs)
Coccidioides
posadasii
Coccidioides
immitis
Aspergillus flavus
PLD_CORPS
Uncinocarpus
reesii
Fusarium
oxysporum
Gibberella
moniliformis
Ajellomyces
capsulatus
Aspergillus flavus
Q2U8X2_ASPOR
SMD2_LOXRE
Coccidioides
posadasii
Coccidioides
immitis
Uncinocarpus
reesii
Fusarium
oxysporum
Gibberella
moniliformis
Ajellomyces
capsulatus
Gibberella
moniliformis
%id
%similarity Align. Weight Score (bits)
50%
65%
282
266
50%
65%
282
266
49%
65%
280
264
45%
63%
274
246
42%
55%
285
198
40%
58%
277
186
38%
53%
251
169
98%
98%
289
585
50%
63%
276
244
50%
63%
276
244
45%
63%
277
229
40%
58%
282
192
38%
55%
276
164
33%
50%
312
145
22%
38%
308
118
The spiders have obtained few hits in this search because the similarity demonstrates a very distant
relationship, and this is same with spider-bacteria values.
The most interesting is that these fungi proteins are “unnamed” and “hypothetical” proteins and don´t
have their molecular function described, as this sequences found have the SmaseD function, they can play
roles in pathogenies acting as virulence or/and penetrance factors, optimizing the parasitism. And the existence
of transcripts of these proteins in databases indicates that this protein similar to SM-specific phospholipase D is
transcribing and translating in the cell, and is playing its function.
Using a new model for search distant homologies:
As the BLASTp isn’t effective to find distant homologues, we used the variant PSI-BLAST because
formation of one specific matrix optimizes the searches. The matrix generated in each iteration give more points
to specific conserved residues in specific positions, as the SMaseD putative active site, that is composed with
seven amino acids (two Histidines, one Lysine, one Tryptophan, two Aspartatic Acids, and one Glutamic Acid).
Because this, the searches using the PSSM (Position Specific Score Matrix) generated by PSI-BLAST were
been more effectives. With this, we found (for example) spiders and ticks using as query the C.
pseudotuberculosis PLD, that are so distant sequences, but both play a common molecular function.
But, the PSI-BLAST can make this sensitive search in proteic level,
and how can we make one so specific search in nucleotide level? Because we comprovate that it exists some
cases of similarities thas can´t be detected through proteic analysis (as searches for ESTs, or in sequencing
genomes). And for makes this sensitive searche in these nucleotide databases, for find more ortholog
sequences, that plays the SmaseD function, we save the matrix gererated through the convergence iteration of
PSI-BLAST. In the next step, we recovered this matrix for use this in a search in a nucleotide level, using the
tBLASTn (that searches in a translated nucleotide database), and as this search uses one PSSM, the algorithm
is named PSI-tBLASTn.
We used for this analysis, two databases of translated nucleotides: the NCBI dbEST, and
CoreNucleotide, that includes gene, WGS sequences and Expressed Sequence Tags. The results were been
interesting, because beyond found all the species related above, we found more great alignments, other
sequences for each species and other sequences for other fungi species that maybe play the same function.
And these other species are phylogenetically related to fungi of this work.
The relation between joined species and utilized algorithm is described in the following Venn Diagram:
PSI-tBLASTn**
Geomyces pannorum*
PSI-BLAST
L. Laeta
L. reculsa, L.similis
L. gaucho, L.boneti Ixodes
scapularis
L. intermedia
L. arizonica
tBLASTn - dbEST
A. gomesiana
R. microplus
R. appendiculatus
T. rubrum
C. posadasii
C. ulcerans
A. oryzae
C.immitis
C. pseudotuberculosis
A. haemolyticum
BLASTp
A. flavus
A. sydowii
H. capsulatum
F. oxysporum
G. moniliformis
U. reesii
+ other
species;
tBLASTn - WGS
+ related species sequences
**using dbEST and NCBI CoreNucleotide databases
This diagram shows that all the species found in the analysis can be found with the search using the
psi-tblastn through only two steps (PSI-TBLASTN against two databases: dbEST and NCBI Core Nucleotide),
and this algorithm can find better alignments for same sequences, because as the tblastn found
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