84-418: IDH may refer to: Isocitrate dehydrogenase Intermediate Disturbance Hypothesis Interactive Data Handler Intradialytic hypotension Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title IDH . If an internal link led you here, you may wish to change the link to point directly to
168-428: A catalase peroxidase which is required to activate Isoniazid. As MDR in M. tuberculosis becomes increasingly common, the emergence of pre-extensively drug resistant (pre-XDR) and extensively drug resistant (XDR-) TB threatens to exacerbate the public health crisis. XDR-TB is characterised by resistance to both rifampin and Isoniazid, as well second-line fluoroquinolones and at least one additional front-line drug. Thus,
252-624: A conserved N-terminal motif, deletion of which impairs growth in macrophages and granulomas. Noncoding RNAs . Nine noncoding sRNAs have been characterised in M. tuberculosis , with a further 56 predicted in a bioinformatics screen. Antibiotic resistance genes . In 2013, a study on the genome of several sensitive, ultraresistant, and multiresistant M. tuberculosis strains was made to study antibiotic resistance mechanisms. Results reveal new relationships and drug resistance genes not previously associated and suggest some genes and intergenic regions associated with drug resistance may be involved in
336-413: A far more recent common ancestor of the M. tuberculosis complex as little as 6000 years ago. An analysis of over 3000 strains of M. bovis from 35 countries suggested an Africa origin for this species. There are currently two narratives existing in parallel regarding the age of MTBC and how it has spread and co-evolved with humans through time. One study compared the M. tuberculosis phylogeny to
420-417: A further nine loci to bring the total to 24. This provides a degree of resolution greater than PFGE and is currently the standard for typing M. tuberculosis . However, with regard to archaeological remains, additional evidence may be required because of possible contamination from related soil bacteria. Antibiotic resistance in M. tuberculosis typically occurs due to either the accumulation of mutations in
504-660: A higher temperature than normal due to the interactions between the two monomeric subunits. The structure of Mycobacterium tuberculosis (Mtb) ICDH-1 bound with NADPH and Mn(2+) bound has been solved by X-ray crystallography. It is a homodimer in which each subunit has a Rossmann fold, and a common top domain of interlocking β sheets. Mtb ICDH-1 is most structurally similar to the R132H mutant human ICDH found in CNS WHO grade 4 astrocytomas , formerly classified as glioblastomas . Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes
588-451: A human host's region of origin is predictive of which TB lineage they carry, which could reflect either a stable association between host populations and specific M. tuberculosis lineages and/or social interactions that are shaped by shared cultural and geographic histories. Regarding the congruence between human and M. tuberculosis phylogenies, a study relying on M. tuberculosis and human Y chromosome DNA sequences to formally assess
672-483: A human mitochondrial genome phylogeny and interpreted these as being highly similar. Based on this, the study suggested that M. tuberculosis , like humans, evolved in Africa and subsequently spread with anatomically modern humans out of Africa across the world. By calibrating the mutation rate of M. tuberculosis to match this narrative, the study suggested that MTBC evolved 40,000–70,000 years ago. Applying this time scale,
756-576: A known structure is the E. coli NADP-dependent IDH, which has only 2 subunits and a 13% identity and 29% similarity based on the amino acid sequences, making it dissimilar to human IDH and not suitable for close comparison. All the known NADP-IDHs are homodimers. Most isocitrate dehydrogenases are dimers, to be specific, homodimers (two identical monomer subunits forming one dimeric unit). In comparing C. glutamicum and E. coli , monomer and dimer, respectively, both enzymes were found to "efficiently catalyze identical reactions." However, C. glutamicum
840-438: A latent state for a prolonged time. Granulomas , organized aggregates of immune cells, are a hallmark feature of tuberculosis infection. Granulomas play dual roles during infection: they regulate the immune response and minimize tissue damage, but also can aid in the expansion of infection. The ability to construct M. tuberculosis mutants and test individual gene products for specific functions has significantly advanced
924-456: A microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system , it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test , acid-fast stain , culture , and polymerase chain reaction . The M. tuberculosis genome was sequenced in 1998. M. tuberculosis requires oxygen to grow , and
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#17327727056271008-423: A remarkably slow growth rate, doubling roughly once per day. Commonly used media include liquids such as Middlebrook 7H9 or 7H12, egg-based solid media such as Lowenstein-Jensen , and solid agar-based such as Middlebrook 7H11 or 7H10 . Visible colonies require several weeks to grow on agar plates. Mycobacteria growth indicator tubes can contain a gel that emits fluorescent light if mycobacteria are grown. It
1092-404: A special nucleoside that acts as an antacid , allowing it to neutralize pH and induce swelling in lysosomes. In M. tuberculosis infections, PPM1A levels were found to be upregulated, and this, in turn, would impact the normal apoptotic response of macrophages to clear pathogens, as PPM1A is involved in the intrinsic and extrinsic apoptotic pathways. Hence, when PPM1A levels were increased,
1176-807: A unique deletion event (tbD1) and thus form a monophyletic group. Types 5 and 6 are closely related to the animal strains of MTBC, which do not normally infect humans. Lineage 3 has been divided into two clades: CAS-Kili (found in Tanzania ) and CAS-Delhi (found in India and Saudi Arabia ). Lineage 4 is also known as the Euro-American lineage. Subtypes within this type include Latin American Mediterranean, Uganda I, Uganda II, Haarlem, X, and Congo. A much cited study reported that M. tuberculosis has co-evolved with human populations, and that
1260-417: Is nonmotile . It divides every 18–24 hours. This is extremely slow compared with other bacteria, which tend to have division times measured in minutes ( Escherichia coli can divide roughly every 20 minutes). It is a small bacillus that can withstand weak disinfectants and can survive in a dry state for weeks. Its unusual cell wall, rich in lipids such as mycolic acid and cord factor glycolipid ,
1344-407: Is a cofactor necessary for this reaction to occur. The metal-ion forms a little complex through ionic interactions with the oxygen atoms on the fourth and fifth carbons (also known as the gamma subunit of isocitrate). After the carbon dioxide is split from the oxalosuccinate in the decarboxylation step (below right), the enol will tautomerize to the keto from. The formation of the ketone double bond
1428-544: Is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis . First discovered in 1882 by Robert Koch , M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid . This coating makes the cells impervious to Gram staining , and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen , or fluorescent stains such as auramine are used instead to identify M. tuberculosis with
1512-437: Is able to persist if either of these pathways is defective, but is attenuated when both pathways are defective. This indicates that intracellular exposure of M. tuberculosis to reactive oxygen and/or reactive nitrogen species results in the formation of DSBs that are repaired by HR or NHEJ. However deficiency of DSB repair does not appear to impair M. tuberculosis virulence in animal models. M. tuberculosis , then known as
1596-557: Is also supported by a study on Lineage 4 relying on genomic aDNA sequences from Hungarian mummies more than 200 years old. In total, the evidence thus favors this more recent estimate of the age of the MTBC most recent common ancestor, and thus that the global evolution and dispersal of M. tuberculosis has occurred over the last 4,000–6,000 years. Among the seven recognized lineages of M. tuberculosis , only two are truly global in their distribution: Lineages 2 and 4. Among these, Lineage 4
1680-427: Is an enzyme that catalyzes the oxidative decarboxylation of isocitrate , producing alpha-ketoglutarate (α-ketoglutarate) and CO 2 . This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol ) to oxalosuccinate (a ketone ), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes
1764-411: Is associated with a relatively poor treatment success rate of 52%. Isoniazid and rifampin resistance are tightly linked, with 78% of the reported rifampin-resistant TB cases in 2019 being resistant to isoniazid as well. Rifampin-resistance is primarily due to resistance-conferring mutations in the rifampin-resistance determining region (RRDR) within the rpoB gene. The most frequently observed mutations of
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#17327727056271848-537: Is common in GWAS, the variants discovered have moderate effect sizes. As an intracellular pathogen , M. tuberculosis is exposed to a variety of DNA-damaging assaults, primarily from host-generated antimicrobial toxic radicals. Exposure to reactive oxygen species and/or reactive nitrogen species causes different types of DNA damage including oxidation, depurination, methylation, and deamination that can give rise to single- and double-strand breaks (DSBs). DnaE2 polymerase
1932-518: Is considered to have a genetic component. A group of rare disorders called Mendelian susceptibility to mycobacterial diseases was observed in a subset of individuals with a genetic defect that results in increased susceptibility to mycobacterial infection. Early case and twin studies have indicated that genetic components are important in host susceptibility to M. tuberculosis . Recent genome-wide association studies (GWAS) have identified three genetic risk loci, including at positions 11p13 and 18q11. As
2016-759: Is distinguished from other mycobacteria by its production of catalase and niacin . Other tests to confirm its identity include gene probes and MALDI-TOF . Analysis of Mycobacterium tuberculosis via scanning electron microscope shows the bacteria are 2.71 ± 1.05 μm in length with an average diameter of 0.345 ± 0.029 μm . The outer membrane and plasma membrane surface areas were measured to be 3.04 ± 1.33 µm and 2.67 ± 1.19 µm , respectively. The cell, outer membrane, periplasm, plasma membrane, and cytoplasm volumes were 0.293 ± 0.113 fl (= μm ), 0.006 ± 0.003 fl , 0.060 ± 0.021 fl , 0.019 ± 0.008 fl , and 0.210 ± 0.091 fl , respectively. The average total ribosome number
2100-459: Is likely responsible for its resistance to desiccation and is a key virulence factor . Other bacteria are commonly identified with a microscope by staining them with Gram stain . However, the mycolic acid in the cell wall of M. tuberculosis does not absorb the stain. Instead, acid-fast stains such as Ziehl–Neelsen stain , or fluorescent stains such as auramine are used. Cells are curved rod-shaped and are often seen wrapped together, due to
2184-422: Is much detailed knowledge about this bacterial enzyme, and it has been found that most isocitrate dehydrogenases are similar in structure and therefore also in function. This similarity of structure and function gives a reason to believe that the structures are conserved as well as the amino acids. Therefore, the active sites amongst most prokaryotic isocitrate dehydrogenase enzymes should be conserved as well, which
2268-487: Is observed throughout many studies done on prokaryotic enzymes. Eukaryotic isocitrate dehydrogenase enzymes on the other hand, have not been fully discovered yet. Each dimer of IDH has two active sites. Each active site binds a NAD /NADP molecule and a divalent metal ion (Mg ,Mn ). In general, each active site has a conserved sequence of amino acids for each specific binding site. In Desulfotalea psychrophila ( Dp IDH) and porcine ( Pc IDH) there are three substrates bound to
2352-459: Is started by the deprotonation of that oxygen off the alpha carbon (C#2) by the same lysine that protonated the oxygen in the first place. The lone pair of electrons moves down kicking off the lone pairs that were making the double bond. This lone pair of electrons abstracts a proton off the Tyrosine that deprotonated the carboxyl group in the decarboxylation step. The reason that we can say that
2436-578: Is technically easier to perform and allows better discrimination between strains. This method makes use of the presence of repeated DNA sequences within the M. tuberculosis genome. Three generations of VNTR typing for M. tuberculosis are noted. The first scheme, called exact tandem repeat, used only five loci, but the resolution afforded by these five loci was not as good as PFGE. The second scheme, called mycobacterial interspersed repetitive unit, had discrimination as good as PFGE. The third generation (mycobacterial interspersed repetitive unit – 2) added
2520-541: Is the most well dispersed, and almost totally dominates in the Americas. Lineage 4 was shown to have evolved in or in the vicinity of Europe, and to have spread globally with Europeans starting around the 13th century. This study also found that Lineage 4 tuberculosis spread to the Americas shortly after the European discovery of the continent in 1492, and suggests that this represented the first introduction of human TB on
2604-465: Is through air droplets originating from a person who has the disease either coughing, sneezing, speaking, or singing. When in the lungs, M. tuberculosis is phagocytosed by alveolar macrophages , but they are unable to kill and digest the bacterium. Its cell wall is made of cord factor glycolipids that inhibit the fusion of the phagosome with the lysosome , which contains a host of antibacterial factors. Specifically, M. tuberculosis blocks
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2688-486: Is upregulated in M. tuberculosis by several DNA-damaging agents, as well as during infection of mice. Loss of this DNA polymerase reduces the virulence of M. tuberculosis in mice. DnaE2 is an error-prone DNA repair polymerase that appears to contribute to M. tuberculosis survival during infection. The two major pathways employed in repair of DSBs are homologous recombinational repair (HR) and nonhomologous end joining (NHEJ). Macrophage-internalized M. tuberculosis
2772-400: The M. tuberculosis complex (MTBC) has a number of members infecting various animal species, these include M. africanum , M. bovis (Dassie's bacillus), M. caprae , M. microti , M. mungi, M. orygis , and M. pinnipedii . This group may also include the M. canettii clade. These animal strains of MTBC do not strictly deserve species status, as they are all closely related and embedded in
2856-729: The Central Asian (CAS) strains; lineage 4 includes the Ghana and Haarlem (H/T), Latin America - Mediterranean (LAM) and X strains; types 5 and 6 correspond to M. africanum and are observed predominantly and at high frequencies in West Africa . A seventh type has been isolated from the Horn of Africa. The other species of this complex belong to a number of spoligotypes and do not normally infect humans. Lineages 2, 3 and 4 all share
2940-464: The H37Rv strain was published in 1998. Its size is 4 million base pairs, with 3,959 genes; 40% of these genes have had their function characterized, with possible function postulated for another 44%. Within the genome are also six pseudogenes . Fatty acid metabolism . The genome contains 250 genes involved in fatty acid metabolism, with 39 of these involved in the polyketide metabolism generating
3024-559: The Levant . M. tuberculosis is a clonal organism and does not exchange DNA via horizontal gene transfer . Despite an additionally slow evolution rate, the emergence and spread of antibiotic resistance in M. tuberculosis poses an increasing threat to global public health. In 2019, the WHO reported the estimated incidence of antibiotic resistant TB to be 3.4% in new cases, and 18% in previously treated cases. Geographical discrepancies exist in
3108-580: The M. tuberculosis complex are all clonal in their spread. The main human-infecting species have been classified into seven lineages. Translating these lineages into the terminology used for spoligotyping, a very crude genotyping methodology, lineage 1 contains the East African - Indian (EAI), the Manila family of strains and some Manu (Indian) strains; lineage 2 is the Beijing group; lineage 3 includes
3192-536: The M. tuberculosis phylogeny, but for historic reasons, they currently hold species status. The M. canettii clade – which includes M. prototuberculosis – is a group of smooth-colony Mycobacterium species. Unlike the established members of the M. tuberculosis group, they undergo recombination with other species. The majority of the known strains of this group have been isolated from the Horn of Africa. The ancestor of M. tuberculosis appears to be M. canettii , first described in 1969. The established members of
3276-450: The adenines at their targeted sequence, some strains of M. tuberculosis carry mutations in MamA that cause partial methylation of targeted adenine bases. This occurs as intracellular stochastic methylation, where a some targeted adenine bases on a given DNA molecule are methylated while others remain unmethylated. MamA mutations causing intercellular mosaic methylation are most common in
3360-446: The chemical reactions : The overall free energy for this reaction is -8.4 kJ/mol. Within the citric acid cycle , isocitrate , produced from the isomerization of citrate, undergoes both oxidation and decarboxylation . The enzyme isocitrate dehydrogenase (IDH) holds isocitrate within its active site using the surrounding amino acids , including arginine , tyrosine , asparagine , serine , threonine , and aspartic acid . In
3444-542: The most recent common ancestor of the M. tuberculosis complex evolved between 40,000 and 70,000 years ago. However, a later study that included genome sequences from M. tuberculosis complex members extracted from three 1,000-year-old Peruvian mummies, came to quite different conclusions. If the most recent common ancestor of the M. tuberculosis complex were 40,000 to 70,000 years old, this would necessitate an evolutionary rate much lower than any estimates produced by genomic analyses of heterochronous samples, suggesting
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3528-527: The " tubercle bacillus ", was first described on 24 March 1882 by Robert Koch , who subsequently received the Nobel Prize in Physiology or Medicine for this discovery in 1905; the bacterium is also known as "Koch's bacillus". M. tuberculosis has existed throughout history, but the name has changed frequently over time. In 1720, though, the history of tuberculosis started to take shape into what
3612-509: The Lys and Tyr residues will be the same from the previous step is because they are helping in holding the isocitrate molecule in the active site of the enzyme. These two residues will be able to form hydrogen bonds back and forth as long as they are close enough to the substrate . The isocitrate dehydrogenase enzyme as stated above produces alpha-ketoglutarate, carbon dioxide, and NADH + H /NADPH + H . There are three changes that occurred throughout
3696-503: The Mn isocitrate porcine IDH complex to deprotonate the alcohol off the alpha-carbon atom. The oxidation of the alpha-C also takes place in this picture where NAD accepts a hydride resulting in oxalosuccinate. Along with the sp to sp stereochemical change around the alpha-C, there is a ketone group that is formed from the alcohol group. The formation of this ketone double bond allows for resonance to take place as electrons coming down from
3780-681: The PPM1A-JNK signalling axis pathway, then, it could eliminate M. tuberculosis -infected macrophages. The ability to restore macrophage apoptosis to M. tuberculosis -infected ones could improve the current tuberculosis chemotherapy treatment, as TB drugs can gain better access to the bacteria in the niche. thus decreasing the treatment times for M. tuberculosis infections. Symptoms of M. tuberculosis include coughing that lasts for more than three weeks, hemoptysis , chest pain when breathing or coughing, weight loss, fatigue, fever, night sweats, chills, and loss of appetite. M. tuberculosis also has
3864-518: The T cells and inhibited their proliferation, cytokine production, and ability to kill target cells. The following is a list of human isocitrate dehydrogenase isozymes: Each NADP -dependent isozyme functions as a homodimer: The isocitrate dehydrogenase 3 isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit: Mycobacterium tuberculosis Tubercle bacillus Koch 1882 Mycobacterium tuberculosis (M. tb), also known as Koch's bacillus ,
3948-598: The active site. Specific mutations in the isocitrate dehydrogenase gene IDH1 have been found in several tumor types, notably brain tumors including astrocytoma and oligodendroglioma . Patients whose tumor had an IDH1 mutation had longer survival compared to patients whose tumor had an IDH1 wild type . Furthermore, mutations of IDH2 and IDH1 were found in up to 20% of cytogenetically normal acute myeloid leukemia (AML). These mutations are known to produce D-2-hydroxyglutarate from alpha-ketoglutarate. D-2-hydroxyglutarate accumulates to very high concentrations which inhibits
4032-401: The age of antibiotic resistance. Inhibition of MmpL3 function showed an inability to transport trehalose monomycolate - an essential cell wall lipid - across the plasma membrane. The recently reported structure of MmpL3 revealed resistance-conferring mutations to associate primarily with the transmembrane domain. Although resistance to pre-clinical MmpL3 inhibitors has been detected, analysis of
4116-441: The bacteria isolated from each person belong to different types, then transmission from B to A is definitively disproven; however, if the bacteria are the same strain, then this supports (but does not definitively prove) the hypothesis that B infected A. Until the early 2000s, M. tuberculosis strains were typed by pulsed field gel electrophoresis . This has now been superseded by variable numbers of tandem repeats (VNTR), which
4200-455: The bridging molecule, early endosomal autoantigen 1 ( EEA1 ); however, this blockade does not prevent fusion of vesicles filled with nutrients. In addition, production of the diterpene isotuberculosinol prevents maturation of the phagosome. The bacteria also evades macrophage-killing by neutralizing reactive nitrogen intermediates. More recently, M. tuberculosis has been shown to secrete and cover itself in 1-tuberculosinyladenosine (1-TbAd),
4284-451: The citric acid cycle) and alpha-ketoglutarate, and competitive feedback inhibition by ATP . A conserved ncRNA upstream of the icd gene which codes for NADP -dependent isocitrate dehydrogenase (IDH) has been reported in bacterial genomes, due to its characteristics this ncRNA resembles previous regulatory motifs called riboswitches , icd-II ncRNA motif has been proposed as a strong candidate riboswitch. Isocitrate dehydrogenase catalyzes
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#17327727056274368-594: The codons in RRDR are 531, 526 and 516. However, alternative more elusive resistance-conferring mutations have been detected. Isoniazid function occurs through the inhibition of mycolic acid synthesis through the NADH-dependent enoyl-acyl carrier protein (ACP)-reductase. This is encoded by the inhA gene. As a result, isoniazid resistance is primarily due to mutations within inhA and the KatG gene or its promoter region -
4452-623: The continent (although animal strains have been found in human remains predating Columbus. Similarly, Lineage 4 was found to have spread from Europe to Africa during the Age of Discovery , starting in the early 15th century. It has been suggested that ancestral mycobacteria may have infected early hominids in East Africa as early as three million years ago. DNA fragments from M. tuberculosis and tuberculosis disease indications were present in human bodies dating from 7000 BC found at Atlit-Yam in
4536-462: The correlation between them, concluded that they are not congruent. Also, a more recent study which included genome sequences from M. tuberculosis complex members extracted from three 1,000-year-old Peruvian mummies, estimated that the most recent common ancestor of the M. tuberculosis complex lived only 4,000 – 6,000 years ago. The M. tuberculosis evolutionary rate estimated by the Bos et al. study
4620-435: The development of alternative therapeutic measures is of utmost priority. An intrinsic contributor to the antibiotic resistant nature of M. tuberculosis is its unique cell wall. Saturated with long-chain fatty acids or mycolic acids, the mycobacterial cell presents a robust, relatively insoluble barrier. This has led to its synthesis being the target of many antibiotics - such as Isoniazid. However, resistance has emerged to
4704-466: The expression of it inhibits the two apoptotic pathways. With kinome analysis, the JNK/AP-1 signalling pathway was found to be a downstream effector that PPM1A has a part to play in, and the apoptotic pathway in macrophages are controlled in this manner. As a result of having apoptosis being suppressed, it provides M. tuberculosis with a safe replicative niche, and so the bacteria are able to maintain
4788-479: The formation of α-hydroxyglutarate. The IDH step of the citric acid cycle is often (but not always) an irreversible reaction due to its large negative change in free energy. It must therefore be carefully regulated to avoid depletion of isocitrate (and therefore an accumulation of alpha-ketoglutarate). The reaction is stimulated by the simple mechanisms of substrate availability (isocitrate, NAD or NADP , Mg / Mn ), product inhibition by NADH (or NADPH outside
4872-626: The function of enzymes that are dependent on alpha-ketoglutarate. This leads to a hypermethylated state of DNA and histones, which results in different gene expression that can activate oncogenes and inactivate tumor-suppressor genes. Ultimately, this may lead to the types of cancer described above. Somatic mosaic mutations of this gene have also been found associated to Ollier disease and Maffucci syndrome . However, recent studies have also shown that D-2-hydroxyglutarate may be converted back into alpha-ketoglutarate either enzymatically or non-enzymatically. Further studies are required to fully understand
4956-545: The genes targeted by the antibiotic or a change in titration of the drug. M. tuberculosis is considered to be multidrug-resistant (MDR TB) if it has developed drug resistance to both rifampicin and isoniazid, which are the most important antibiotics used in treatment. Additionally, extensively drug-resistant M. tuberculosis (XDR TB) is characterized by resistance to both isoniazid and rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). The genome of
5040-481: The globally successful Beijing sublineage of M. tuberculosis. Due to the influence of methylation on gene expression at some locations in the genome, it has been hypothesized that IMM may give rise to phenotypic diversity, and partially responsible for the global success of Beijing sublineage. The M. tuberculosis complex evolved in Africa and most probably in the Horn of Africa . In addition to M. tuberculosis ,
5124-437: The incidence rates of drug-resistant TB. Countries facing the highest rates of ABR TB China, India, Russia, and South Africa. Recent trends reveal an increase in drug-resistant cases in a number of regions, with Papua New Guinea, Singapore, and Australia undergoing significant increases. Multidrug-resistant Tuberculosis (MDR-TB) is characterised by resistance to at least the two front-line drugs isoniazid and rifampin . MDR
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#17327727056275208-414: The intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=IDH&oldid=1202455447 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Isocitrate dehydrogenase Isocitrate dehydrogenase ( IDH ) ( EC 1.1.1.42 ) and ( EC 1.1.1.41 )
5292-411: The leaving carboxylate group move towards the ketone. The decarboxylation of oxalosuccinate (below center) is a key step in the formation of alpha-ketoglutarate. In this reaction, the lone pair on the adjacent Tyrosine hydroxyl abstracts the proton off the carboxyl group. This carboxyl group is also referred to as the beta subunit in the isocitrate molecule. The deprotonation of the carboxyl group causes
5376-403: The leaving group, detaches from the beta carbon of isocitrate (C3) and the electrons flow to the ketone oxygen attached to the alpha carbon, granting a negative charge to the associated oxygen atom and forming an alpha-beta unsaturated double bond between carbons 2 and 3. The fourth and final box illustrates step 3, which is the saturation of the alpha-beta unsaturated double bond that formed in
5460-518: The lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis , especially during the chronic phase of infection when other nutrients are likely not available. PE/PPE gene families . About 10% of the coding capacity is taken up by the PE / PPE gene families that encode acidic, glycine-rich proteins. These proteins have
5544-418: The lone pair of electrons to move down making carbon dioxide and separating from oxalosuccinate. The electrons continue to move towards the alpha carbon pushing the double bond electrons (making the ketone) up to abstract a proton off an adjacent lysine residue. An alpha-beta unsaturated double bond results between carbon 2 and three. As you can see in the picture, the green ion represents either Mg or Mn , which
5628-581: The macrophage niche. JNK plays a key role in the control of apoptotic pathways—intrinsic and extrinsic. In addition, it is also found to be a substrate of PPM1A activity, hence the phosphorylation of JNK would cause apoptosis to occur. Since PPM1A levels are elevated during M. tuberculosis infections, by inhibiting the PPM1A signalling pathways, it could potentially be a therapeutic method to kill M. tuberculosis -infected macrophages by restoring its normal apoptotic function in defence of pathogens. By targeting
5712-478: The majority of them. A novel, promising therapeutic target is mycobacterial membrane protein large 3 (MmpL3). The mycobacterial membrane protein large (MmpL) proteins are transmembrane proteins which play a key role in the synthesis of the cell wall and the transport of the associated lipids. Of these, MmpL3 is essential; knock-out of which has been shown to be bactericidal. Due to its essential nature, MmpL3 inhibitors show promise as alternative therapeutic measures in
5796-409: The next step) will flow from the nearby carboxyl group and push the electrons of the double bonded oxygen up onto the oxygen atom itself, which collects a proton from a nearby lysine . The third box illustrates step 2, which is the decarboxylation of oxalosuccinate . In this step, the carboxyl group oxygen is deprotonated by a nearby tyrosine , and those electrons flow down to C2. Carbon dioxide,
5880-427: The potential of spreading to other parts of the body. This can cause blood in urine if the kidneys are affected, and back pain if the spine is affected. Typing of strains is useful in the investigation of tuberculosis outbreaks, because it gives the investigator evidence for or against transmission from person to person. Consider the situation where person A has tuberculosis and believes he acquired it from person B. If
5964-422: The presence of fatty acids in the cell wall that stick together. This appearance is referred to as cording, like strands of cord that make up a rope. M. tuberculosis is characterized in tissue by caseating granulomas containing Langhans giant cells , which have a "horseshoe" pattern of nuclei. M. tuberculosis can be grown in the laboratory. Compared to other commonly studied bacteria, M. tuberculosis has
6048-541: The previous step. The negatively charged oxygen (attached to the alpha-carbon) donates its electrons, reforming the ketone double bond and pushing another lone pair (the one that forms the double bond between the alpha and beta carbons) "off" the molecule. This lone pair, in turn, picks up a proton from the nearby tyrosine. This reaction results in the formation of alpha-ketoglutarate, NADH + H /NADPH + H , and CO 2 . Two aspartate amino acid residues (below left) are interacting with two adjacent water molecules (w6 and w8) in
6132-411: The provided figure, the first box shows the overall isocitrate dehydrogenase reaction. The necessary reactants for this enzyme mechanism are isocitrate, NAD / NADP , and Mn or Mg . The products of the reaction are alpha-ketoglutarate , carbon dioxide , and NADH + H / NADPH + H . Water molecules help to deprotonate the oxygen atoms of isocitrate. The second box in the figure illustrates step 1 of
6216-433: The reaction, which is the oxidation of the alpha-carbon (C2 here, also called alpha-C). In this process, the alcohol group of the alpha-carbon is deprotonated and the resulting lone pair of electrons forms a ketone group on that carbon. NAD /NADP acts as an electron-accepting cofactor and collects the resulting hydride from C2. The oxidation of the alpha carbon introduces a molecular arrangement where electrons (in
6300-540: The reaction. The oxidation of Carbon 2, the decarboxylation (loss of carbon dioxide) off Carbon 3, and the formation of a ketone group with a stereochemical change from sp to sp . The Isocitrate Dehydrogenase (IDH) enzyme structure in Escherichia coli was the first IDH ortholog structure to be elucidated and understood. Since then, the Escherichia coli IDH structure has been used by most researchers to make comparisons to other isocitrate dehydrogenase enzymes. There
6384-736: The resistance to more than one drug. Noteworthy is the role of the intergenic regions in the development of this resistance, and most of the genes proposed in this study to be responsible for drug resistance have an essential role in the development of M. tuberculosis . Epigenome . Single-molecule real-time sequencing and subsequent bioinformatic analysis has identified three DNA methyltransferases in M. tuberculosis, M ycobacterial A denine M ethyltransferases A (MamA), B (MamB), and C (MamC ). All three are adenine methyltransferases , and each are functional in some clinical strains of M. tuberculosis and not in others. Unlike DNA methyltransferases in most bacteria, which invariably methylate
6468-428: The roles of IDH1 mutation (and D-2-hydroxyglutarate) in cancer. Recent research highlighted cancer-causing mutations in isocitrate dehydrogenase which may cause accumulation of the metabolite D-2-hydroxyglutarate (D-2HG). Notarangelo et al. showed that such high concentrations of D-2HG could act as a direct inhibitor of lactate dehydrogenase in mouse T cells. Inhibition of this metabolic enzyme altered glucose metabolism in
6552-539: The study found that the M. tuberculosis effective population size expanded during the Neolithic Demographic Transition (around 10,000 years ago) and suggested that M. tuberculosis was able to adapt to changing human populations and that the historical success of this pathogen was driven at least in part by dramatic increases in human host population density. It has also been demonstrated that after emigrating from one continent to another,
6636-473: The third step of the citric acid cycle while converting NAD to NADH in the mitochondria . The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP as a cofactor instead of NAD . They localize to the cytosol as well as the mitochondrion and peroxisome . The NAD-IDH is composed of 3 subunits, is allosterically regulated, and requires an integrated Mg or Mn ion. The closest homologue that has
6720-601: The understanding of its pathogenesis and virulence factors . Many secreted and exported proteins are known to be important in pathogenesis. For example, one such virulence factor is cord factor (trehalose dimycolate), which serves to increase survival within its host. Resistant strains of M. tuberculosis have developed resistance to more than one TB drug, due to mutations in their genes. In addition, pre-existing first-line TB drugs such as rifampicin and streptomycin have decreased efficiency in clearing intracellular M. tuberculosis due to their inability to effectively penetrate
6804-473: The waxy coat. Such large numbers of conserved genes show the evolutionary importance of the waxy coat to pathogen survival. Furthermore, experimental studies have since validated the importance of a lipid metabolism for M. tuberculosis , consisting entirely of host-derived lipids such as fats and cholesterol. Bacteria isolated from the lungs of infected mice were shown to preferentially use fatty acids over carbohydrate substrates. M. tuberculosis can also grow on
6888-497: The widespread mutational landscape revealed a low level of environmental resistance. This suggests that MmpL3 inhibitors currently undergoing clinical trials would face little resistance if made available. Additionally, the ability of many MmpL3 inhibitors to work synergistically with other antitubercular drugs presents a ray of hope in combatting the TB crisis. The nature of the host-pathogen interaction between humans and M. tuberculosis
6972-423: Was 1672 ± 568 with ribosome density about 716.5 ± 171.4/(0.1 fl) . M. tuberculosis is part of a genetically related group of Mycobacterium species that has at least 9 members: Humans are the only known reservoirs of M. tuberculosis . A misconception is that M. tuberculosis can be spread by shaking hands, making contact with toilet seats, sharing food or drink, or sharing toothbrushes. However, major spread
7056-452: Was recorded as having ten times as much activity than E. coli and seven times more affinitive/specific for NADP. C. glutamicum favored NADP over NAD . In terms of stability with response to temperature, both enzymes had a similar Tm or melting temperature at about 55 °C to 60 °C. However, the monomer C. glutamicum showed a more consistent stability at higher temperatures, which was expected. The dimer E. coli showed stability at
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