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Ancient genes in contemporary persistent microbial pathogens.


For the first 2 billion years of microbial life, the earth's atmosphere and hydrosphere had a vanishingly small oxygen concentration, so extant life must have been essentially anaerobic. The nature of this early life was unclear until studies beginning in 1966 on the bacterium Chlorobium limicola forma thiosulphatophilum led to the discovery of a metabolic network that has come to be known as the reductive citric acid (rTCA) cycle (Evans et al., 1966). This pathway has also been found in Aquifex (Beh et al., 1993), Hydrogeneobacter (Shiba et al, 1985), and Desulfobacter (Schauder et al., 1987). The chief function of the cycle is to incorporate carbon from carbon dioxide into the cell's organic compounds. Citrate lyase converts citric acid into acetyl-CoA and oxaloacetic acid. A minor loop goes from acetyl-CoA to pyruvate to oxaloacetate, thus yielding two oxaloacetates from each citrate (Fig. 1A). The two oxaloacetates continue around the cycle and, by yielding two citrates for each original citrate, constitute an autocatalytic network. Energy must be supplied from outside the cycle by environmental oxidation-reduction reactions. The cycle serves as an engine of synthesis instead of one of energy transformation as in most aerobes. In autotrophs, all the anabolic pathways begin in this cycle.

"Some two billion years ago, the cyanobacteria that are oxygen-releasing, photo synthetic prokaryotes began the increase in concentration of atmospheric oxygen from far less than one part per thousand to about 200 parts per thousand ..." (Margulis and Schwartz, 1998). After the accumulation of oxygen from this photosynthetic bacterial metabolism (Summons et al., 1999; Brocks et al, 1999), organisms began to use the citric acid cycle in the oxidative direction. This is the familiar Krebs cycle, or tricarboxylic acid (TCA) cycle, that is the core of most contemporary intermediary metabolism. In this role the cycle oxidizes acetate to carbon dioxide and water while yielding reduced NADH (nicotinamide adenine dinucleotide) and FAD[H.sub.2] (flavin adenine dinucleotide) for bioenergetic purposes (Fig. 1B). This cycle still serves as the center of biosynthetic pathways, especially in autotrophs. Since the atmosphere contained very little oxygen for the first 2 billion years after the origin of life, it can be argued that reductive metabolism preceded the oxidative. The simplicity of chemoautotrophy compared to photoautotrophy also suggests that the former preceded the latter. Smith and Morowitz (2004) and Wachtershauser (1990) theorize that the reductive TCA cycle operated in primitive autotrophs. In any case, the same citric acid cycle can be engaged in either a reductive or oxidative direction if the appropriate energy sources are available. Since many of the reactions are reversible, the reductive cycle appears to require two key enzymes not present in the oxidative cycle: citrate lyase and 2-oxoglutarate synthase. The organism Desulfobacter hydrogenophilus can operate as either an oxidative heterotroph, requiring organic substrates, or a reductive autotroph (Moller et al., 1987). In addition, there is the reductive acetyl-CoA pathway (Fig. 1C), which "may be used also in the oxidative direction for the complete oxidation of acetyl-CoA in those heterotrophic anaerobes which do not have the enzymes of a complete oxidative citric acid cycle." (Fuchs, 1989).

The enormous rise in atmospheric oxygen concentration about 2500 million years ago, presumably due to oxygenic photosynthesis, led to a decline of anaerobes, which survived by occupying residual niches with a low concentration of oxygen (Kasting, 2001; Anbar and Knoll, 2002; Catling et al, 2005; Kerr, 2005). Thus, microbes became aerobes, anaerobes, and in-between physiological forms. The horizontal migration of genes allowed for organisms with the potential for living in either environment (Gogarten and Townsend, 2005). These conditions required adjustment in both the energy pathways and the biosynthetic pathways to key building blocks.

Metabolite flux and reversal of TCA cycle

An example of a process that includes both oxidative and reductive steps is anaerobic fermentation by the yeast Saccharomyces cervisiae (Camaresa et al., 2003), such as in wine production. The yeast begin by using glycolysis and the tricarboxylic cycle to provide energy for all the cellular processes. When oxygen gets low, the yeast shift to alcoholic fermentation, going from pyruvate to ethanol and carbon dioxide. Fermentation provides sufficient energy but lacks the intermediates necessary for the citric acid cycle to synthesize cellular components such as succinate. Succinate can be made reductively, if aspartate is the nitrogen source, or oxidatively, when glutamate is the nitrogen source (Fig. 2A). A similar example has been noted by Reed et al. (2003) in a simulation-based metabolic model of Escherichia coli. The model predicts efficient, completely anaerobic growth on 2-oxoglutarate, due to the citrate lyase enzyme. Under progressively oxygen-limiting growth conditions, the reactions that convert 2-oxoglutarate to oxaloacetate are used more heavily by first reversing some of the steps of the TCA cycle to generate citrate, which is split into acetate and oxaloacetate by citrate lyase (Fig. 2B). Indeed, the citric acid cycle in facultative anaerobes such as Escherichia coli is known to be feedback-inhibited by 2-oxoglutarate, specifically through the allosteric deactivation of citrate synthase (Damson et al., 1979). These observations suggest that, depending on the growth conditions, the citric acid cycle--or part of the cycle--may be used oxidatively or reductively to provide the anabolic steps in the survival and growth of the organism.

Materials and Methods

Information regarding the presence of the rTCA cycle enzymes in the organisms whose genomes have been completely sequenced was obtained by data mining the Kyoto Encyclopedia of Genes and Genomes (KEGG) database--an on-line, public domain, open-source collection of databases that includes metabolic pathways, genome sequences, and analysis (Kanehisa, 1997; Kanehisa and Goto, 2000). The KEGG PATHWAY Database ( was utilized for retrieval of all information, using the search criteria related to "metabolism," "energy metabolism," "reductive carboxylate cycle (C[O.sub.2] fixation)," and the entries for each of the enzymes mentioned therein. Numbers in parentheses following enzyme names in the sections that follow are assigned by the Enzyme Commission of the International Union of Biochemistry and Molecular Biology on the basis of the reactions that they catalyze.

Results and Discussion

Table 1 lists prokaryotes that are known from sequence studies to contain citrate lyase (EC and 2-oxoglu-tarate synthase (EC Organisms having both enzymes should be able to drive the entire citric acid cycle reductively; with only one of the two, they might be able to drive part of the reductive cycle. As seen from the yeast case, the ability to drive the cycle both ways might be of value when there is alteration or transient perturbation in the environment. By enabling the organisms to adapt to a changing milieu, this ability could ensure survival and propagation--not only for free-living organisms, but especially for those that have adapted to intracellular residence in suitable hosts. This may be of clinical relevance in dealing with microbial pathogenicity in cases where some of the infectious agents are able to adapt, survive, and persist in privileged physiological niches, well protected from defense mechanisms of the host, for protracted periods.

Latent tuberculosis and pathogen survival in granuloma

A case in point is found in Mycobacterium tuberculosis infections. After being inhaled, those invading pathogens that are phagocytosed by alveolar macrophages can survive and even replicate in the phagosomal compartment, assimilating carbon and producing energy. Subsequently, the progressive escalation in the immune response culminates in the formation of granulomas, organized collections of activated macrophages and other immune cells (Stewart et al., 2003). The pathogen persists within these granulomas during this containment phase of the long-term asymptomatic infection, until a compromising change in the immune status of the host results in containment failure. At that point the center of the granuloma undergoes necrotic degradation, or caseation, causing lesions and liberating infectious bacilli, the hallmark of latent tuberculosis (Manabe and Bishai, 2000; Russell, 2001; Cosma et al., 2003). Within the dynamic environment of the lesions, a continuum seems to exist between replication of metabolically active bacteria and phagocytic killing, maintaining a steady-state (Bouley et al., 2001). The implication is that successful persistence requires that the rate of growth and the rate of thermal decay of the bacteria be balanced, and equilibrium can occur only when there is negative feedback (Blaser and Kirchner, 1999). This phenomenon raises a major intriguing question of how the bacteria survive within these lesions, an issue that may be directly related to the mechanisms by which the pathogen adapts to environmental changes--beginning with the invasion, then progressing to intracellular residence in the phagosomal compartments of macrophages and eventually in the interior of the granulomas.

Persistence by adaptation to changing environments

Mycobacterium tuberculosis can alter its mode of metabolism to survive in hostile and austere interior environments that are progressively nutrient-starved, microaerophilic, and oxygen-depleted (Gomez and McKinney, 2004; Voskuil et al., 2004; Wayne and Sohaskey, 2001). An organism that utilizes alternative energy sources must be able to maintain the balance of oxidative and reductive reactions in the metabolic scheme. Reducing equivalents of NADH (reduced nicotinamide adenine dinucleotide), NADPH (reduced nicotinamide adenine dinucleotide phosphate), and FAD[H.sub.2] (reduced flavin adenine dinucleotide) generated under aerobic conditions via glycolysis, the Krebs cycle, and [beta]-oxidation pathways could be reoxidized efficiently through the electron-transport chain, terminating with oxygen. However, under oxygen-limiting microaerophilic and anaerobic conditions, severe restrictions may be imposed on the reoxidation potential, leading to redox imbalance that results in toxic accumulations of the reducing equivalents. Because the lesions are enriched in C[O.sub.2] (Haapanen et al, 1959), the reductive TCA cycle, with its remarkable ability to fix carbon solely from C[O.sub.2], may allow these reducing equivalents to be used efficiently in the anabolic mode. Since this organism has both of the key enzymes for the rTCA cycle (Table 1), a fully functional cycle in the reverse direction may be able to fix carbon in the relatively reductive environment, maintaining replication at a low level that facilitates persistence anaerobically.

This may well be a common theme in the survival strategy among bacteria that cause persistent infections, including Salmonella enterica serovar Typhi and Helicobacter pylori (Monack et al., 2004a). Hosts chronically infected with Salmonella harbor the pathogen within the reticuloendothelial system for long periods of time. The bacteria are inside the classical granulomatous lesions that arise in the spleen, liver, and gall bladder, and in the mesenteric lymph nodes (MLNs) that are the most common site of chronic infection (Vasquez-Torres et al., 1999; Monack et al., 2004b). In low numbers, the persistent bacteria colonize the interior of macrophages residing in the MLNs (Monack et al, 2004b). H. pylori, a gram-negative, microaerophilic bacteria, colonizes the upper gastrointestinal tract of humans and plays a causative role in the development of chronic gastritis, gastric and duodenal ulcers, and gastric adenocarcinoma. The bacterium proliferates in the mucous layer of the stomach, and its invasion of the gastric epithelium results in the recruitment of macrophages, polymorphonuclear phagocytes, and lymphocytes to the gastric mucosa. In spite of this host response, the pathogen can persist for decades (Blaser and Atherton, 2004). Again, like the Mycobacteria and Salmonella, H. pylori cells ingested by macrophages manage to survive and replicate intracellularly, excluded from immune surveillance, and to persist and distribute themselves in multiple locales in the gastric ecosystem throughout the life of the host (Allen et al., 2000).

Carbon fixation and restoration of redox balance by rTCA cycle

The ability of these persistent pathogens to survive and proliferate through extracellular and intracellular phases in varying hostile environments of the host requires novel metabolic strategies for carbon fixation. The reductive TCA cycle may provide such a strategy, facilitating anaerobic carbon fixation and restoring redox balance. Most enzymes of the cycle are shared in both the oxidative and reductive directions, with citrate lyase (EC and 2-oxoglutarate synthase (EC being the key enzymes for the complete reductive mode. Examination of the genomes of Mycobacteria has revealed the presence of both the above-mentioned enzymes of the rTCA cycle in M. tuberculosis and M. bovis, while Salmonella typhi and H. pylori have, respectively, citrate lyase and 2-oxoglutarate synthase, along with the rest of the enzymes (Tables 1 and 2). Similarly, a number of other pathogenic bacteria also seem to possess one of the two marker enzymes of the reductive TCA cycle (Table 2).

Key enzymes of rTCA cycle as drug targets

As we have seen, the bacteria responsible for many persistent microbial infections must sustain the stress of encountering varied and unfavorable conditions in the host, respond with alternate metabolic strategies, and adapt to the environmental transitions and alterations. Under nutritional stress and microaerophilic and anaerobic conditions, a partial or fully functional reductive TCA cycle could depending on the metabolite balance, permit carbon acquisition, ensuring survival and proliferation of the microbe. It is possible that such a mechanism functions in these persistent bacterial infections. Biochemical investigations with bacteria grown under the appropriate microaerophilic or anaerobic conditions should establish whether the rTCA cycle is operative in these organisms. If it is, the rTCA cycle would be a point of vulnerability that could be exploited for therapeutic intervention. The key enzymes citrate lyase and 2-oxoglutarate synthase would qualify as candidates to be targeted in a mechanism-based search for new therapeutic agents. The absence of these two enzymes in the host and closely related organisms further enhances their suitability as drug targets; gene disruption or knockout studies could be used to reveal their functional significance and essentiality in persistent microbial pathogenesis.

Acquisition of ancient genes by horizontal gene transfer

It is intriguing that rTCA cycle genes that are central to the metabolism of the most ancient organisms--the chemolithoautotrophs of the reductive world, which are placed at the deep end of the root of the phylogenetic tree (Burggraf et al., 1992)--are revealed to be present in evolutionarily very distant organisms (see Tables 1 and 2). Besides their predominant distribution in actinobacteria and proteobacteria, the genes of the rTCA cycle (including one or both of the key enzymes) are found in a number of organisms of the archaeal kingdom. The major forces that shape the prokaryotic genomes and influence the gene content are gene genesis, gene loss, and horizontal gene transfer (HGT)--a process by which genomes acquire sequences from organisms that may be distantly related (Boucher et al., 2003). HGT is also believed to contribute a major source of genetic diversity in bacteria (Woese, 2002). In light of the wide diversity and distribution of both archaea and bacteria, it is possible that these bacteria have acquired these ancient genes through HGT. Thus the genomes of archaea may serve as a source of genes essential to the metabolic flexibility of bacteria, including the persistent pathogens. Incorporation of such metabolic capabilities into their gene pool may confer innovative adaptational strategies for survival in diverse environments and make it possible to select even hostile host niches by breaching host barriers that exclude other organisms. Thus archaea, which by themselves are nonpathogenic, might have indirectly contributed to bacterial pathogenicity.

It seems strange indeed that enzymes thought to be associated with very early organisms near the root of the taxonomic tree turn up in vertebrate pathogens as possible elements of persistent infection. It is an example of the inter-relatedness of all biology--an association that is further reified by horizontal gene transfer.


We are indebted to the Sir John Templeton Foundation for support.

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Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, 22030

Received 23 May 2005; accepted 17 October 2005.

* To whom correspondence should be addressed. E-mail:
Table 1 Organisms that contain both the key enzymes of the reductive
TCA cycle, citrate lyase (EC. and 2-oxoglutarate synthase

KEGG Abbreviation and Lineage of Organism

MTU*  Bacteria  Actinobacteria  Mycobacterium tuberculosis H37Rv (lab
MBO*  Bacteria  Actinobacteria  Mycobacterium bovis
MTC*  Bacteria  Actinobacteria  Mycobacterium tuberculosis CDC1551
SCO   Bacteria  Actinobacteria  Streptomyces coelicolor
SMA   Bacteria  Actinobacteria  Streptomyces avermitilis
HAL   Archaea   Euryarchaeota   Halobacterium sp. NRC-1
APE   Archaea   Crenarchaeota   Aeropyrum pemix
SSO   Archaea   Crenarchaeota   Sulfolobus solfataricus
STO   Archaea   Crenarchaeota   Sulfolobus tokodaii

* Indicates pathogenic bacteria
Source: KEGG Pathways Database 2004-2005.

Table 2 Organisms that contain either of the two key enzymes of the
reductive TCA cycle, citrate lyase (EC. or 2-oxoglutarate
synthase (EC.

KEGG Abbreviation and Lineage of Organism

Organisms that contain citric lyase (EC.
ECO    Bacteria  Proteobacteria           Escherichia coli K-12 MG1655
ECJ    Bacteria  Proteobacteria           Escherichia coli K-12 W3110
ECE*   Bacteria  Proteobacteria           Escherichia coli O157:H7
ECS*   Bacteria  Proteobacteria           Escherichia coli O157:H7 Sakai
ECC*   Bacteria  Proteobacteria           Escherichia coli CFT073
STY*   Bacteria  Proteobacteria           Salmonella typhi CT18
STT*   Bacteria  Proteobacteria           Salmonella typhi Ty2
STM*   Bacteria  Proteobacteria           Salmonella typhimurium LT2
YPE*   Bacteria  Proteobacteria           Yersinia pestis CO92
SFL*   Bacteria  Proteobacteria           Shigella flexneri 301
SFX*   Bacteria  Proteobacteria           Shigella flexneri 2457T
HIN*   Bacteria  Proteobacteria           Haemophilus influenzae
HDU*   Bacteria  Proteobacteria           Haemophilus ducreyi
VCH*   Bacteria  Proteobacteria           Vibrio cholerae El
PAE*   Bacteria  Proteobacteria           Pseudomonas aeruginosa PA01
BPE    Bacteria  Proteobacteria           Bordetella pertussis Tohama I
BPA    Bacteria  Proteobacteria           Bordetella parapertussis
BBR    Bacteria  Proteobacteria           Bordetella bronchiseptica
NEU    Bacteria  Proteobacteria           Nitrosomonas europaea
BME*   Bacteria  Proteobacteria           Brucella melitensis 16M
BMS*   Bacteria  Proteobacteria           Brucella suis 1330
LLA    Bacteria  Firmicutes               Lactococcus lactis subsp.
                                            lactis IL 1403
SPY*   Bacteria  Firmicutes               Streptococcus pyogenes SF370
SPM*   Bacteria  Firmicutes               Streptococcus pyogenes
SPG*   Bacteria  Firmicutes               Streptococcus pyogenes MGAS315
SPS*   Bacteria  Firmicutes               Streptococcus pyogenes SSI-1
SMU*   Bacteria  Firmicutes               Streptococcus mutans UA159
LPL    Bacteria  Firmicutes               Lactobacillus plantarum WCFS1
EFA*   Bacteria  Firmicutes               Enterococcus faecalis V583
CPE*   Bacteria  Firmicutes               Clostridium perfringens 13
CTC*   Bacteria  Firmicutes               Clostridium tetani E88
MTU*   Bacteria  Actinobacteria           Mycobacterium tuberculosis
MTC*   Bacteria  Actinobacteria           Mycobacterium tuberculosis
MBO*   Bacteria  Actinobacteria           Mycobacterium bovis subsp.
                                            bovis AF2122/97
CGL    Bacteria  Actinobacteria           Corynebacterium glutamicum
CEF    Bacteria  Actinobacteria           Corynebacterium efficiens
SCO    Bacteria  Actinobacteria           Streptomyces coelicolor A3(2)
SMA    Bacteria  Actinobacteria           Streptomyces avermitilis
FNU    Bacteria  Fusobacteria             Fusobacterium nucleatum ATCC
LIL*   Bacteria  Spirochete               Leptospira interrogans 56601
DRA    Bacteria  Radioresistant bacteria  Deinococcus radiodurans R1
HAL    Archaea   Euryarchaeota            Halobacterium sp. NRC-1
APE    Archaea   Crenarcheota             Aeropyrum pernix K1
SSO    Archaea   Crenarcheota             Sulfolobus solfataricus
STO    Archaea   Crenarcheota             Sulfolobus tokodaii strain7

Organisms that contain 2-oxoglutarate synthase (EC.
HPY*   Bacteria  Proteobacteria           Helicobacter pylori 26695
HPJ*   Bacteria  Proteobacteria           Helicobacter pylori J99
HHE*   Bacteria  Proteobacteria           Helicobacter hepaticus ATCC
CJE*   Bacteria  Proteobacteria           Campylobacter jejuni NCTC11168
BHA    Bacteria  Firmicutes               Bacillus halodurans C-125
BAN*   Bacteria  Firmicutes               Bacillus anthracis Ames
BCE*   Bacteria  Firmicutes               Bacillus cereus ATCC 14579
SAU*   Bacteria  Firmicutes               Staphylococcus aureus N315
SAV*   Bacteria  Firmicutes               Staphylococcus aureus Mu50,
                                            MRSA & vancomycin resistant
SAM*   Bacteria  Firmicutes               Staphylococcus aureus MW2
SEP*   Bacteria  Firmicutes               Staphylococcus epidermidis
CAC    Bacteria  Firmicutes               Clostridium acetobutylicum
TTE    Bacteria  Firmicutes               Thermoanaerobacter
MTU*   Bacteria  Actinobacteria           Mycobacterium tuberculosis
MTC*   Bacteria  Actinobacteria           Mycobacterium tuberculosis
MBO*   Bacteria  Actinobacteria           Mycobacterium bovis subsp.
                                            bovis AF2122/97
SCO    Bacteria  Actinobacteria           Streptomyces coelicolor A3(2)
SMA    Bacteria  Actinobacteria           Streptomyces avermitilis
RBA    Bacteria  Planctomyces             Rhodopirellula baltica
BTH*   Bacteria  Bacteriod                Bacteroides thetaiotaomicron
CTE    Bacteria  Green sulfur             Chlorobium tepidum TLS
TMA    Bacteria  Hyperthermophilic        Thermotoga maritime MSB8
MJA    Archaea   Euryarchaeota            Methanococcus jannaschii
MAC    Archaea   Euryarchaeota            Methanosarcina acetivorans C2A
MMA    Archaea   Euryarchaeota            Methanosarcina mazei Goel
MTH    Archaea   Euryarchaeota            Methanobacterium
                                            thermoautotrophicum deltaH
MKA    Archaea   Euryarchaeota            Methanopyrus kandleri AV19
AFU    Archaea   Euryarchaeota            Archaeoglobus fulgidus VC-16
HAL    Archaea   Euryarchaeota            Halobacterium sp. NRC-1
TAC    Archaea   Euryarchaeota            Thermoplasma acidophilum
TVO    Archaea   Euryarchaeota            Thermoplasma volcanium GSS1
PHO    Archaea   Euryarchaeota            Pyrococcus horikoshii OT3
PAB    Archaea   Euryarchaeota            Pyrococcus abyssi GE5
PFU    Archaea   Euryarchaeota            Pyrococcus furiosus DSM 3638
APE    Archaea   Crenarcheota             Aeropyrum pernix K1
SSO    Archaea   Crenarcheota             Sulfolobus solfataricus
STO    Archaea   Crenarcheota             Sulfolobus tokodaii strain7
PAI    Archaea   Crenarchaeota            Pyrobaculum aerophilum 1M2

* Indicates pathogenic bacteria.
Source: KEGG Pathway Database, 2004-2005.
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Author:Srinivasan, Vijayasarathy; Morowitz, Harold J.
Publication:The Biological Bulletin
Geographic Code:1USA
Date:Feb 1, 2006
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