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Vol. 9, Issue 12, 1175-1183, December 1999
RESEARCH
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
RESULTS AND DISCUSSION
METHODS
REFERENCES
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In previous studies we determined the nucleotide sequence of the
gene cluster containing lys20, hacA (lys4A),
hacB (lys4B), orfE, orfF,
rimK, argC, and argB of Thermus
thermophilus, an extremely thermophilic bacterium. In this study,
we characterized the role of each gene in the cluster by gene
disruption and examined auxotrophy in the disruptants. All disruptants
except for the orfE disruption showed a lysine auxotrophic
phenotype. This was surprising because this cluster consists of genes
coding for unrelated proteins based on their names, which had been
tentatively designated by homology analysis. Although the newly found
pathway contains 
-aminoadipic acid as a lysine biosynthetic
intermediate, this pathway is not the same as the eukaryotic one. When
each of the gene products was phylogenetically analyzed, we found that
genes evolutionarily-related to the lysine biosynthetic genes in
T. thermophilus were all present in a hyperthermophilic and
anaerobic archaeon, Pyrococcus horikoshii, and formed a gene
cluster in a manner similar to that in T. thermophilus. Furthermore, this gene cluster was analogous in part to the present leucine and arginine biosyntheses pathways. This lysine biosynthesis cluster is assumed to be one of the origins of lysine biosynthesis and
could therefore become a key to the evolution of amino acid biosynthesis.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
RESULTS AND DISCUSSION
METHODS
REFERENCES
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Lysine had been believed to be synthesized from
aspartic acid through the diaminopimelic acid (DAP) pathway in all
prokaryotic organisms. An extremely thermophilic Gram-negative
bacterium, Thermus thermophilus, was shown to synthesize
lysine not via DAP, but from 2-oxoglutaric acid and acetyl-CoA through
the -aminoadipic acid (AAA) pathway, (Fig. 1)
which is known to be common in fungi (Kosuge and Hoshino 1998
; Kobashi
et al. 1999). Because higher eukaryotes other than animals synthesize
lysine through DAP, the AAA pathway is a characteristic that
distinguishes fungi from higher eukaryotes (Vogel 1964, 1965; Broquist
1971).
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In general, prokaryotes biosynthesize not only lysine but also
methionine, threonine, and isoleucine from aspartic acid. T. thermophilus also possesses an aspartate kinase (Kobashi et al. 1999) that catalyzes the first reaction in the DAP pathway. However, this enzyme is only used for synthesis of methionine, threonine, and
probably isoleucine. In T. thermophilus, lysine is synthesized through the AAA pathway (Kobashi et al. 1999; Kosuge and Hoshino 1998).
This was the first discovery of lysine biosynthesis via AAA in
bacteria. Here we report that the gene cluster for lysine biosynthesis
through the AAA pathway is also found in a hyperthermophilic and
anaerobic archaeon, Pyrococcus horikoshii, whose genome has been sequenced completely (Kawarabayasi et al. 1998), and discuss the
evolution of amino acid biosynthesis.
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RESULTS AND DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
RESULTS AND DISCUSSION
METHODS
REFERENCES
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Lysine Biosynthetic Cluster in T. thermophilus
We characterized the role of each gene in the cluster by gene
disruption (Kosuge and Hoshino 1997, 1998) and examined auxotrophy of
the disruptants (Fig. 2). Because the genes in the
cluster are closely arranged in the same orientation, the cluster seems to be an operon. Gene disruption by inserting a kanamycin-resistance gene could cause reduced expression of a distal gene, which might be
required for lysine biosynthesis in an operon. At present, it is
unclear whether or not the genes are transcribed in a single mRNA and
have independent promoters. In any case, to weaken the possible polar
effect, the kanamycin-resistance gene cassette and the promoter were
inserted in the same orientation as the gene cluster, which may allow
expression of the genes located downstream via a read-through
transcript originated from the inserted promoter. All of the
disruptants, except for those with orfE disruption, showed a
lysine auxotrophic phenotype (Table 1). This shows
that all of the genes except for orfE are involved in lysine
biosynthesis. This was surprising because this cluster consists of
genes coding for apparently unrelated proteins, as judged by their
names, which were tentatively assigned by homology analysis.
Considering the functions of the homologs of the gene products and
auxotrophy of the disruptants, lys20 was shown to encode
homocitrate synthase, and hacA and hacB to code for
large and small subunits of homoaconitase, respectively (Kosuge and
Hoshino 1998; Kobashi et al. 1999). Based on auxotrophy of the
disruptants and the homology of the gene products, we assume that the
ribosomal protein S6 modification enzyme (RimK),
N-acetylglutamate kinase (ArgB), and
N-acetylglutamate 5-semialdehyde dehydrogenase (ArgC) are
involved in modification of AAA, phosphotransfer to the AAA derivative,
and its reduction to yield an aldehyde compound, respectively (see
below). This clearly indicates that the AAA pathway for lysine
biosynthesis is used in prokaryotes as well as in eukaryotes, although
some modification must be present. We also found the cluster of lysine biosynthetic genes in P. horikoshii but in no other organism
in the international DNA/protein databases (EMBL, GenBank, and DDBJ).
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Phylogenetic Analysis of Components in the AAA Pathway of T. thermophilus
The above results let us reconsider amino acid biosynthesis. We here phylogenetically analyze each protein encoded by the lys20, hacA, hacB, rimK, argC, and argB genes. The alignment data are available on http://iam.u-tokyo.ac.jp/misyst/lysclust.html.
Homocitrate Synthase of T. thermophilus
Homocitrate synthase catalyzes the reaction to form homocitric acid with 2-oxoglutaric acid and acetyl-CoA. This is the first reaction in the AAA pathway (Fig. 1). Homocitrate synthase of T. thermophilus (Lys20) is grouped with those of the yeasts Saccharomyces cerevisiae and Yarrowia lipolytica (Fig. 3A). In addition, this group is closely related to a protein, PH1727, of P. horikoshii and a protein, LeuA1, of a hyperthermophilic bacterium Aquifex aeolicus (Deckert et al. 1998). The lineage of homocitrate synthase is closely related to
that of 2-isopropylmalate synthase (LeuA). LeuA is involved in the
branched pathway toward leucine and catalyzes the reaction similar to
that of homocitrate synthase, in which 2-isopropylmalic acid is used in
place of 2-oxoglutaric acid as one of the substrates. The phylogenetic
tree shows that homocitrate synthase and 2-isopropylmalate synthase
share a common ancestor.
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Homoaconitase of T. thermophilus
Homoaconitase (homoaconitate hydratase) catalyzes conversion of cis-homoaconitic acid to either homocitric acid or homoisocitric acid, or vice versa. The large subunit of homoaconitase (HacA/Lys4A) of T. thermophilus is grouped with a protein, PH1726, of P. horikoshii (Fig. 3B). This group is connected to the lineage of 3-isopropylmalate dehydratase (LeuC) homologs from A. aeolicus and three archaea, Archaeoglobus fulgidus (Klenk et al. 1997), Methanobacterium thermoautotrophicum (Smith et al. 1997) and Methanococcus jannaschii (Bult et al. 1996). Similar results were obtained with the small subunit,
HacB/Lys4B, of homoaconitase (data not shown).
Each of these three archaea has two 3-isopropylmalate dehydratase
homologs, both of which are also related to HacA of T. thermophilus and PH1726 of P. horikoshii. This may reflect
the past existence of a common origin of homoaconitase and
3-isopropylmalate dehydratase in those microorganisms.
T. thermophilus homoaconitase consists of large and small
subunits, HacA and HacB, like 3-isopropylmalate dehydratase, LeuC and
LeuD, whereas fungal homoaconitase is a single, long polypeptide containing sequences for both large and small subunits. The environment of fungi has been quite different from the extremely thermophilic environment of Thermus and Pyrococcus. In addition,
the phylogenetic tree (Fig. 3B) shows that T. thermophilus
homoaconitase and its homolog of P. horikoshii share an
ancestor with eukaryotic homoaconitases but that they possibly
separated from the eukaryotic enzymes in the early stages of evolution.
All the observations suggest that the homoaconitase gene was not
transferred horizontally from prokaryotes to fungi.
The phylogenetic tree in Figure 3B contains aconitase in addition to
homoaconitase and 3-isopropylmalate dehydratase. Aconitase (aconitate
hydratase) reversibly catalyzes the conversion of cis-aconitic acid to either citric acid or isocitric acid in the citric acid cycle
and therefore shares structural characteristics with homoaconitase and
3-isopropylmalate dehydratase. In this respect, recently Irvin and
Bhattacharjee (1998) also reported that fungal homoaconitase shared a
common ancestor with aconitase and 3-isopropylmalate dehydrogenase.
T. thermophilus RimK-Like Protein
T. thermophilus contains a rimK-like gene within the gene cluster for lysine biosynthesis. The RimK protein of Escherichia coli was isolated and characterized as a protein that adds glutamic acid residues to the carboxyl terminus of ribosomal protein S6 of the organism (Kang et al. 1989). The protein family
including E. coli RimK is defined as a number of proteins with
ATP-dependent carboxylate-amine ligase activity, where acylphosphate
intermediates are involved in the catalytic mechanism (Galperin and
Koonin 1997). The phylogenetic tree (Fig. 4) shows that there are two
major groups: biotin carboxylase, and RimK. The
T. thermophilus RimK homolog is again most closely related to
P. horikoshii PH1721. Other archaea, such as A. fulgidus, M. thermoautotrophicum, and M. jannaschii, have at least two proteins, each of which is classified to the biotin carboxylase or RimK groups. Interestingly, M. jannaschii has two homologs in the RimK subgroup: One is grouped
with those of T. thermophilus and P. horikoshii, and
the other is grouped with those including E. coli RimK.
Considering that RimK-like protein of T. thermophilus is
involved in lysine biosynthesis, the RimK homolog that is grouped with
those of T. thermophilus and P. horikoshii might also
have a similar catalytic activity required for lysine biosynthesis.
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T. thermophilus ArgC and ArgB
ArgC catalyzes the conversion of N-acetylglutamate 5-phosphate to N-acetylglutamate 5-semialdehyde. This is the third reaction in the arginine biosynthetic pathway. By homology search using PSI-BLAST (Altschul et al. 1997) for proteins homologous to that encoded by the argC gene in the lysine biosynthetic gene
cluster of T. thermophilus, we found another gene having the
name argC in the T. thermophilus genome (Baetens et
al. 1998). This shows that T. thermophilus has at least two
argC homologous genes: One is used in arginine biosynthesis,
and the other is used in lysine biosynthesis. Hereafter, we call the
protein working in arginine biosynthesis as true-ArgC, and tentatively
call the protein involved in lysine biosynthesis as pseudo-ArgC.
In the phylogenetic tree (Fig. 5A), T. thermophilus true-ArgC
is grouped with an ArgC homolog of A. aeolicus and those of achaea, while pseudo-ArgC is most closely related to an ArgC homolog, PH1720, of P. horikoshii. P. horikoshii has no other
argC homolog in its complete genome sequence
database. This suggests that ArgC of P. horikoshii is involved in both arginine and lysine biosyntheses. In
any case, it is evident that T. thermophilus (and probably P. horikoshii) lysine biosynthesis is related to the present
arginine biosynthetic pathway.
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; Miller and Bhattacharjee 1996). No significant
similarity in amino acid sequence is observed between aminoadipate
reductase and ArgB/C. Because the lysine biosynthetic pathway in
T. thermophilus is suggested to proceed in a mechanism similar
to that in arginine biosynthesis, we assume that a 2-aminoadipic acid
derivative possibly modified by a RimK homolog is converted to a
6-semialdehyde derivative by pseudo-ArgC and ArgB in the lysine
biosynthetic gene cluster. Thus, the lysine biosynthetic pathway in
T. thermophilus may not be completely the same as that in the eukaryotes.
Horizontal Gene Transfer Between Thermus and Pyrococcus?
As described above, all the enzymes encoded in the lysine biosynthetic gene cluster in T. thermophilus are closely related to the proteins in P. horikoshii. Surprisingly, the corresponding genes in P. horikoshii are grouped in a manner similar to T. thermophilus (Fig. 6). Here, we mention the possibility of horizontal gene-cluster transfer between T. thermophilus and P. horikoshii, each of which live in a hyper-thermogenic environment, because only T. thermophilus and P. horikoshii have similar lysine biosynthetic gene clusters among the 19 organisms examined. All the phylogenetic trees show that the gene cluster for lysine biosynthesis in T. thermophilus and P. horikoshii are closely related to each other.
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reported that 24% of the predicted coding sequences in
the Thermotoga maritima genome were most similar to proteins
in archaeal species, and almost half were similar to P. horikoshii. However, T. maritima does not have the gene
cluster for AAA lysine biosynthesis but has the lysA gene for
DAP lysine biosynthesis.
Amino Acid Biosynthesis of P. horikoshii
Although P. horikoshii does not have a gene manipulation
system, its amino acid biosynthesis can be deduced by analysis of phylogenetic trees and by use of genetic evidence from T. thermophilus, whose lysine gene organization is similar.
Diaminopimelic acid decarboxylase (LysA) catalyzes
meso-2,6-diaminopimelic acid to lysine. This is the last
reaction in the biosynthesis from aspartic acid to lysine (Fig. 1). The
homology search using PSI-BLAST reveals that P. horikoshii has
no LysA homolog. This is consistent with the idea that P. horikoshii synthesizes lysine not through DAP, but via the AAA
pathway like T. thermophilus. When the gene clusters are
compared between T. thermophilus and P. horikoshii,
both organisms possess a single additional gene, orfE and
PH1722, in the cluster (Fig. 6). We do not know the function
of OrfE. However, the amino acid sequence of OrfE is homologous to that
of OrfF, which is required for lysine biosynthesis in T. thermophilus. Interestingly, both OrfE and OrfF are composed of
repetitive short segments of 20-30 amino acids, all of which contained
a C-P/E-x-C-G motif. We speculate that gene duplication of
orfF may have occurred. PH1722 has high amino acid sequence
similarity to 3-isopropylmalate dehydrogenase (LeuB) and isocitrate
dehydrogenase (data not shown). By analogy of the reactions mediated by
these enzymes, we assume that PH1722 possesses homoisocitrate
dehydrogenase activity. P. horikoshii possesses no other
homologs of PH1722, PH1724, PH1726, and PH1727 in its genome. This
suggests that these four proteins might be involved in leucine
biosynthesis as LeuB, LeuD, LeuC, and LeuA, respectively, as well as
lysine biosynthesis, as P. horikoshii was reported to show
only Trp auxotrophy (Gonzalez et al. 1998). It should be noted that
these enzymes are structurally similar to enzymes consisting of a part
of the citric acid cycle (Fig. 1). Considering that the earliest
organisms are believed to have lived under hot, anaerobic conditions,
it is reasonable to postulate that amino acid biosynthesis developed
earlier than the citric acid cycle, which functions under aerobic
conditions. It is possible that the aconitase of the tricarboxylic acid
(TCA) cycle evolved from homoaconitase or 3-isopropylmalate dehydratase.
In addition to the four genes PH1722, PH1724, PH1726, and PH1727, P. horikoshii has single argC and argB homologs in its genome. Furthermore, the archaeon has argD (PH1716) and argE (PH1715) homologs, which may have the activities of aminotransferase and deacylase just downstream of the putative argB gene PH1718. By analogy to arginine biosynthesis, we assume that the semialdehyde-type AAA derivative formed by PH1720 and PH1718 could be converted to lysine by the ArgD and ArgE homologs in P. horikoshii. The organism contains only a single copy of argC, argB, argD, and argE homologs in its genome. We therefore speculate that the products of these genes may possess the activity required for arginine biosynthesis.
Although P. horikoshii and T. thermophilus have very
similar clusters of lysine biosynthetic genes, it is unlikely that
these organisms have identical synthetic pathways, because T. thermophilus has at least two argC homologs while P. horikoshii has a single argC homolog. This suggests that
lysine and arginine biosyntheses are separated in T. thermophilus. Consistent with this, the argB disruptant of
T. thermophilus requires only lysine for its growth, but not
arginine (Table 1). In this study, it is suggested that P. horikoshii might have developed unique amino acid biosynthetic systems in which several amino acids are synthesized by a limited number of enzymes with broad substrate specificity. The presence of
lysine biosynthesis through AAA is suggested for an extremely thermophilic anaerobic archaeon, Thermoproteus neutrophilus,
based on acetate assimilation patterns (Schäfer et al. 1989). It
is therefore interesting to elucidate the lysine biosynthetic pathway of T. neutrophilus.
Evolution of Amino Acid Biosynthesis
P. horikoshii grows optimally under anaerobic conditions at
a temperature of nearly 100°C. Considering that the earliest
organisms had lived under hot and anaerobic conditions,
Pyrococcus may preserve prototypic proteins. The enzyme
recruitment model for the evolution of metabolic pathways suggests the
enzymes which are somewhat loose in their substrate specificity could
initially function in multiple pathways and evolve late into two or
more specific enzymes by gene duplication (Jensen 1976). In fact,
several enzymes from Pyrococcus are reported to have broad
substrate specificity (Kengen at al. 1993; Bauer et al. 1996; Fischer
et al. 1996; Mai and Adams 1996; Durbecq et al. 1997; Glasemacher et
al. 1997). In this study we propose that P. horikoshii, like
T. thermophilus, synthesizes lysine through the AAA pathway.
We further suggest that unlike T. thermophilus, at least four
of these lysine genes are also involved in leucine synthesis and four
other genes in that cluster are involved in arginine synthesis. This
system suggested for P. horikoshii could be one of the
earliest amino acid biosynthetic systems, in which enzymes recognized
at least two different substrates.
Interestingly, the other archaea, A. fulgidus, M. thermoautotrophicum, and M. jannaschii, each have two or three homologs of lys20, hacA, and hacB. The phylogenetic trees (Fig. 2A,B) show that each gene was duplicated or triplicated at an early stage of evolution, probably before the species diverged. At present, we do not know the homologs' physiological substrates. However, it may be possible to speculate that some of them are still in a stage of evolution seeking for enhancing substrate specificity. Pyrococcus has lived on the earth for a long time under hot and anaerobic conditions, which may allow the organism to have some prototypic enzymes. In this study we propose a hypothesis that the present biosynthetic pathways for lysine, leucine, and arginine could have developed by ancestor enzymes with broad substrate specificity. We believe that further studies on the amino acid biosynthetic systems in P. horikoshii will help elucidate the evolution of amino acid biosynthesis.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
RESULTS AND DISCUSSION
METHODS
REFERENCES
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T. thermophilus was transformed as described (Koyama et
al. 1986). Disruption of each gene was performed according to the method of Kosuge and Hoshino (1997, 1998). Each disruption was confirmed by Southern hybridization. The detailed data are available on request.
We performed a homology search using PSI-BLAST (Altschul et al. 1997)
with the given parameter values on the DNA data bank of Japan (DDBJ).
This program compares a given query amino acid sequence against all
other proteins in the databases to identify related sequences. Here the
query amino acid sequences were AAA lysine biosynthesis-related
proteins from T. thermophilus. Each of the multiple alignments
was created using the CLUSTAL W program (Thompson et al. 1994) on DDBJ
among a query sequence and high-scoring sequences of the PSI-BLAST
result. The phylogenetic tree from p-distance estimation by the
neighbor-joining method (Saitou and Nei 1987) with 1000 bootstrap
analyses (Felsenstein 1985) was constructed based on the multiple
alignment using MEGA version 1.01 (Kumar et al. 1993).
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ACKNOWLEDGMENTS |
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We thank Dr. Tetsuo Hamamoto for providing helpful comments for completing the draft.
The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.
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NOTE |
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We renamed lys20, hacA (lys4A), hacB (lys4B), orfE, orfF, rimK, argC, and argB in the cluster of T. thermophilus, as lysS, lysT, lysU, lysV, lysW, lysX, lysY, and lysZ, respectively, because the cluster is actually involved in lysine biosynthesis.
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FOOTNOTES |
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4 Corresponding author.
E-MAIL umanis{at}mail.ecc.u-tokyo.ac.jp; FAX 81-3-5841-8030.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
RESULTS AND DISCUSSION
METHODS
REFERENCES
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-glucosidase and -mannosidase from the hyperthermophilic archaeon Pyrococcus furiosus. Purification, characterization, gene cloning, and sequence analysis.
J. Biol. Chem.
271:
23749-23755-glucosidase from the extremophile Pyrococcus furiosus in glucoconjugate synthesis.
Biotechnology
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88-91[CrossRef][Medline].-glucosidase from the hyperthermophilic archaeon Pyrococcus furiosus.
Eur. J. Biochem.
213:
305-312[Medline].-aminoadipic acid not via diaminopimelic acid.
J. Bacteriol.
181:
1713-1718-aminoadipate pathway in Thermus thermophilus.
FEMS Microbiol. Lett.
169:
361-367[Medline].
H: Functional analysis and comparative genomics.
J. Bacteriol.
179:
7135-7155Received July 13, 1999; accepted in revised form October 14, 1999.
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