Isocitrate lyase

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Isocitrate Lyase
Isocitrate lyase.png
Homotetrameric structure of Isocitrate lyase from E. coli. Based on PDB 1IGW. [1]
Identifiers
EC no. 4.1.3.1
CAS no. 9045-78-7
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins
Isocitrate lyase family
Identifiers
SymbolICL
Pfam PF00463
InterPro IPR000918
PROSITE PDOC00145
SCOP2 1f8m / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Isocitrate lyase (EC 4.1.3.1), or ICL, is an enzyme in the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate. [2] [3] Together with malate synthase, it bypasses the two decarboxylation steps of the tricarboxylic acid cycle (TCA cycle) and is used by bacteria, fungi, and plants. [4]

Contents

The systematic name of this enzyme class is isocitrate glyoxylate-lyase (succinate-forming). Other names in common use include isocitrase, isocitritase, isocitratase, threo-Ds-isocitrate glyoxylate-lyase, and isocitrate glyoxylate-lyase. This enzyme participates in glyoxylate and dicarboxylate metabolism.

Mechanism

This enzyme belongs to the family of lyases, specifically the oxo-acid-lyases, which cleave carbon-carbon bonds. Other enzymes also belong to this family including carboxyvinyl-carboxyphosphonate phosphorylmutase (EC 2.7.8.23) which catalyses the conversion of 1-carboxyvinyl carboxyphosphonate to 3-(hydrohydroxyphosphoryl) pyruvate carbon dioxide, and phosphoenolpyruvate mutase (EC 5.4.2.9), which is involved in the biosynthesis of phosphinothricin tripeptide antibiotics.

During catalysis, isocitrate is deprotonated, and an aldol cleavage results in the release of succinate and glyoxylate. This reaction mechanism functions much like that of aldolase in glycolysis, where a carbon-carbon bond is cleaved and an aldehyde is released. [5]

ICL catalyzed rxn.png

In the glyoxylate cycle, malate synthase then catalyzes the condensation of glyoxylate and acetyl-CoA to form malate so the cycle can continue.

ICL competes with isocitrate dehydrogenase, an enzyme found in the TCA cycle, for isocitrate processing. Flux through these enzymes is controlled by phosphorylation of isocitrate dehydrogenase, which has a much higher affinity for isocitrate as compared to ICL. [6] Deactivation of isocitrate dehydrogenase by phosphorylation thus leads to increased isocitrate channeling through ICL, as seen when bacteria are grown on acetate, a two-carbon compound. [6]

Enzyme structure

As of 2023, multiple structures of ICL have been solved. These include one structure from Pseudomonas aeruginosa (PDB accession code 6G1O), one structure from Fusarium graminearum (5E9H), one structure from fungus Aspergillus nidulans (1DQU), one structure from Yersinia pestis (3LG3), one structure from Burkholderia pseudomallei (3I4E), one structure from Escherichia coli (1IGW), two structures from Magnaporthe oryzae (5E9F and 5E9G), four structures from Brucella melitensis (3P0X, 3OQ8, 3EOL and 3E5B) and eleven structures from Mycobacterium tuberculosis (1F61, 1F8I, 1F8M, 6C4A, 6C4C, 5DQL, 6EDW, 6EDZ, 6EE1, 6XPP and 8G8K).

ICL is composed of four identical chains and requires a Mg2+ or Mn2+ and a thiol for activity. [4] In Escherichia coli , Lys-193, Lys-194, Cys-195, His-197, and His-356 are thought to be catalytic residues, while His-184 is thought to be involved in the assembly of the tetrameric enzyme. [7]

Between prokaryotes and eukaryotes, a difference in ICL structure is the addition of approximately 100 amino acids near the center of the eukaryotic enzyme. In eukaryotes, the additional amino acids are thought to function in the localization of ICL to single-membrane-bound organelles called glyoxysomes. [4] [8] These additional amino acids account for the difference in molecular mass: the prokaryotic ICL is 48kDa, while the eukaryotic ICL is 67 kDa. [4] Only one cysteine residue is conserved between the sequences of the fungal, plant and bacterial enzymes; it is located in the middle of a conserved hexapeptide.

Most ICLs that have been characterised to date contain only one domain (the catalytic domain). However, in the isoform 2 of M. tuberculosis ICL, two domains were found. [9] Through structural and kinetic studies, the C-terminal domain was found to be a regulatory domain, which dimerises with the corresponding C-terminal domain from another subunit (of the ICL2 tetramer) upon the binding of acetyl coenzyme A to activate the catalytic activity of the enzyme. [9]

In M. tuberculosis H37Rv (a commonly-used laboratory strain), the gene that encodes ICL2 was split into two open reading frames (rv1915 and rv1916), thus encoding Rv1915 (ICL2a) and Rv1916 (ICL2b) respectively. The biological functions of Rv1915 (ICL2a) and Rv1916 (ICL2b) are poorly understood. Rv1915 and rv1916 were initially characterized as pseudogenes. [10] An in silico study in 2019 predicted that Rv1916 (ICL2b) could be involved in the synthesis of secondary metabolites. [11] In vitro studies showed that both Rv1915 (ICL2a) and Rv1916 (ICL2b) may be able to catalyze the conversion of isocitrate to form succinate and glyoxylate. [11] [12] However, a recent structural and biochemical study showed that Rv1916 (ICL2b) does not have ICL activity. [13] Instead, the study showed that Rv1916 (ICL2b) is a acetyl-CoA-binding protein with unknown biological function. [13]

Assays

Several assays were developed to study the enzyme kinetics and inhibition of ICL. The most frequently-used assays involved the use of chemical or enzyme-coupled ultraviolet–visible (UV/vis) spectroscopy to measure the amount of glyoxylate that is being formed. For example, glyoxylate can be reacted with phenylhydrazine to form hydrazone that can be analysed by UV/vis spectroscopy. [14] Alternatively, lactate dehydrogenase can be used to catalyse the reduction of glyoxylate to glycolate in the presence of nicotinamide adenine dinucleotide (NADH), which is a cosubstrate of lactate dehydrogenase. During the reaction, NADH is being oxidised to NAD+. The decrease in NADH concentration can then measured by UV/vis spectroscopy using a dye. [10] In additional to spectroscopic techniques, biophysical techniques including native non-denaturing mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy have also been applied to study ICL. [15] [16]

Biological function

The ICL enzyme has been found to be functional in various archaea, bacteria, protists, plants, fungi, and nematodes. [17] Although the gene has been found in genomes of nematodes and cnidaria, it has not been found in the genomes of placental mammals. [17]

By diverting isocitrate from the TCA cycle, the actions of ICL and malate synthase in the glyoxylate cycle result in the net assimilation of carbon from 2-carbon compounds. [18] Thus, while the TCA cycle yields no net carbon assimilation, the glyoxylate cycle generates intermediates that can be used to synthesize glucose (via gluconeogenesis), plus other biosynthetic products. As a result, organisms that use ICL and malate synthase are able to synthesize glucose and its metabolic intermediates from acetyl-CoA derived from acetate or from the degradation of ethanol, fatty acids, or poly-β-hydroxybutyrate. [4] This function is especially important for higher plants when using seed oils. In germinating seeds, the breakdown of oils generates acetyl-CoA. This serves as a substrate for the glyoxylate cycle, which generates intermediates which serve as a primary nutrient source prior to the beginning of production of sugars by photosynthesis. [8]

In M. tuberculosis, ICL isoforms 1 and 2 also play the role of methylisocitrate lyase, converting methylisocitrate into succinate and pyruvate. [9] [19] This is important because the methylcitrate cycle is key for the survival of the bacteria on odd-chain fatty acids. [20]

Disease relevance

ICL has found to be important in human, animal, and plant pathogenesis. [4] For several agricultural crops including cereals, cucumbers, and melons, increased expression of the gene encoding ICL is important for fungal virulence. [4] For instance, increased gene expression of icl1 has been seen in the fungus Leptosphaeria maculans upon infection of canola. Inactivation of the icl1 gene leads to reduced pathogenicity of the fungus, which is thought to be a result of the inability of the fungus to use carbon sources provided by the plant. [21]

Additionally, upregulation of the glyoxylate cycle has been seen for pathogens that attack humans. This is the case for fungi such as Candida albicans , which inhabits the skin, mouth, GI tract, gut and vagina of mammals and can lead to systemic infections of immunocompromised patients; as well as for the bacterium Mycobacterium tuberculosis , the major causative agent of tuberculosis. [22] [23] In this latter case, ICL has been found to be essential for survival in the host. [24] Thus, ICL is a current inhibition target for therapeutic treatments of tuberculosis. [25]

Because of its use by pathogenic fungi and bacteria, specific inhibitors are being sought for ICL and malate synthase. [4] Although some inhibitors have already been identified, including itaconate, itaconic anhydride, bromopyruvate, nitropropionate, oxalate, and malate, these are non-specific and would also inhibit other enzymes essential for host function. [4] [26] [27] More research is needed to identify inhibitors that selectively target enzymes in the glyoxylate cycle.

See also

Related Research Articles

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The citric acid cycle —also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Succinic acid</span> Dicarboxylic acid

Succinic acid is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fumarate by the enzyme succinate dehydrogenase in complex 2 of the electron transport chain which is involved in making ATP, and as a signaling molecule reflecting the cellular metabolic state.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Biological carbon fixation</span> Series of interconnected biochemical reactions

Biological carbon fixation or сarbon assimilation is the process by which inorganic carbon is converted to organic compounds by living organisms. The compounds are then used to store energy and as structure for other biomolecules. Carbon is primarily fixed through photosynthesis, but some organisms use a process called chemosynthesis in the absence of sunlight.

<span class="mw-page-title-main">Oxaloacetic acid</span> Organic compound

Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes that occur in animals. It takes part in gluconeogenesis, the urea cycle, the glyoxylate cycle, amino acid synthesis, fatty acid synthesis and the citric acid cycle.

<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. 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 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.

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Glyoxysomes are specialized peroxisomes found in plants (particularly in the fat storage tissues of germinating seeds) and also in filamentous fungi. Seeds that contain fats and oils include corn, soybean, sunflower, peanut and pumpkin. As in all peroxisomes, in glyoxysomes the fatty acids are oxidized to acetyl-CoA by peroxisomal β-oxidation enzymes. When the fatty acids are oxidized hydrogen peroxide (H2O2) is produced as oxygen (O2) is consumed. Thus the seeds need oxygen to germinate. Besides peroxisomal functions, glyoxysomes possess additionally the key enzymes of the glyoxylate cycle (isocitrate lyase and malate synthase) which accomplish the glyoxylate cycle bypass.

<span class="mw-page-title-main">Itaconic acid</span> Chemical compound

Itaconic acid, or methylidenesuccinic acid, is an organic compound. This dicarboxylic acid is a white solid that is soluble in water, ethanol, and acetone. Historically, itaconic acid was obtained by the distillation of citric acid, but currently it is produced by fermentation. The name itaconic acid was devised as an anagram of aconitic acid, another derivative of citric acid.

<span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrates. In microorganisms, the glyoxylate cycle allows cells to use two carbons, such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available. The cycle is generally assumed to be absent in animals, with the exception of nematodes at the early stages of embryogenesis. In recent years, however, the detection of malate synthase (MS) and isocitrate lyase (ICL), key enzymes involved in the glyoxylate cycle, in some animal tissue has raised questions regarding the evolutionary relationship of enzymes in bacteria and animals and suggests that animals encode alternative enzymes of the cycle that differ in function from known MS and ICL in non-metazoan species.

<span class="mw-page-title-main">Mixed acid fermentation</span> Biochemical conversion of six-carbon sugars into acids in bacteria

In biochemistry, mixed acid fermentation is the metabolic process by which a six-carbon sugar is converted into a complex and variable mixture of acids. It is an anaerobic (non-oxygen-requiring) fermentation reaction that is common in bacteria. It is characteristic for members of the Enterobacteriaceae, a large family of Gram-negative bacteria that includes E. coli.

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<span class="mw-page-title-main">Methylisocitrate lyase</span>

The enzyme methylisocitrate lyase catalyzes the chemical reaction

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<span class="mw-page-title-main">Malate synthase</span> Class of enzymes

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Isocitrate lyase family is a family of evolutionarily related proteins.

<span class="mw-page-title-main">Methylcitrate cycle</span>

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References

  1. ↑ Britton KL, Abeysinghe IS, Baker PJ, Barynin V, Diehl P, Langridge SJ, et al. (September 2001). "The structure and domain organization of Escherichia coli isocitrate lyase". Acta Crystallographica. Section D, Biological Crystallography. 57 (Pt 9): 1209–18. doi:10.1107/S0907444901008642. PMID   11526312.
  2. ↑ Beeching JR (December 1989). "High sequence conservation between isocitrate lyase from Escherichia coli and Ricinus communis". Protein Sequences & Data Analysis. 2 (6): 463–6. PMID   2696959.
  3. ↑ Atomi H, Ueda M, Hikida M, Hishida T, Teranishi Y, Tanaka A (February 1990). "Peroxisomal isocitrate lyase of the n-alkane-assimilating yeast Candida tropicalis: gene analysis and characterization". Journal of Biochemistry. 107 (2): 262–6. doi:10.1093/oxfordjournals.jbchem.a123036. PMID   2361956.
  4. 1 2 3 4 5 6 7 8 9 Dunn MF, Ramírez-Trujillo JA, Hernández-Lucas I (October 2009). "Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis". Microbiology. 155 (Pt 10): 3166–75. doi: 10.1099/mic.0.030858-0 . PMID   19684068.
  5. ↑ Garrett R, Grisham CN (2008). Biochemistry . Brooks Cole. pp.  588. ISBN   978-0-495-10935-8.
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  8. 1 2 Eastmond PJ, Graham IA (February 2001). "Re-examining the role of the glyoxylate cycle in oilseeds". Trends in Plant Science. 6 (2): 72–8. doi:10.1016/S1360-1385(00)01835-5. PMID   11173291.
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  10. 1 2 Höner Zu Bentrup K, Miczak A, Swenson DL, Russell DG (December 1999). "Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis". Journal of Bacteriology. 181 (23): 7161–7. doi:10.1128/JB.181.23.7161-7167.1999. PMC   103675 . PMID   10572116.
  11. 1 2 Antil M, Sharma J, Brissonnet Y, Choudhary M, Gouin S, Gupta V (September 2019). "Structure function insights into elusive Mycobacterium tuberculosis protein Rv1916" (PDF). International Journal of Biological Macromolecules. 141: 927–936. doi:10.1016/j.ijbiomac.2019.09.038. PMID   31505209. S2CID   202556684.
  12. ↑ Antil M, Gupta V (June 2022). "Rv1915 and Rv1916 from Mycobacterium tuberculosis H37Rv form in vitro protein-protein complex". Biochimica et Biophysica Acta (BBA) - General Subjects. 1866 (6): 130130. doi:10.1016/j.bbagen.2022.130130. PMID   35307510.
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  17. 1 2 Kondrashov FA, Koonin EV, Morgunov IG, Finogenova TV, Kondrashova MN (October 2006). "Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation". Biology Direct. 1 (31): 31. doi: 10.1186/1745-6150-1-31 . PMC   1630690 . PMID   17059607.
  18. ↑ Kornberg HL, Krebs HA (May 1957). "Synthesis of cell constituents from C2-units by a modified tricarboxylic acid cycle". Nature. 179 (4568): 988–91. Bibcode:1957Natur.179..988K. doi:10.1038/179988a0. PMID   13430766. S2CID   40858130.
  19. ↑ Gould TA, van de Langemheen H, Muñoz-Elías EJ, McKinney JD, Sacchettini JC (August 2006). "Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis". Molecular Microbiology. 61 (4): 940–7. doi: 10.1111/j.1365-2958.2006.05297.x . PMID   16879647. S2CID   26099043.
  20. ↑ Eoh H, Rhee KY (April 2014). "Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids". Proceedings of the National Academy of Sciences of the United States of America. 111 (13): 4976–81. Bibcode:2014PNAS..111.4976E. doi: 10.1073/pnas.1400390111 . PMC   3977286 . PMID   24639517.
  21. ↑ Idnurm A, Howlett BJ (October 2002). "Isocitrate lyase is essential for pathogenicity of the fungus Leptosphaeria maculans to canola (Brassica napus)". Eukaryotic Cell. 1 (5): 719–24. doi:10.1128/EC.1.5.719-724.2002. PMC   126752 . PMID   12455691.
  22. ↑ Lorenz MC, Bender JA, Fink GR (October 2004). "Transcriptional response of Candida albicans upon internalization by macrophages". Eukaryotic Cell. 3 (5): 1076–87. doi:10.1128/EC.3.5.1076-1087.2004. PMC   522606 . PMID   15470236.
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  24. ↑ Muñoz-Elías EJ, McKinney JD (June 2005). "Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence". Nature Medicine. 11 (6): 638–44. doi:10.1038/nm1252. PMC   1464426 . PMID   15895072.
  25. ↑ Bhusal RP, Bashiri G, Kwai BX, Sperry J, Leung IK (July 2017). "Targeting isocitrate lyase for the treatment of latent tuberculosis". Drug Discovery Today. 22 (7): 1008–1016. doi:10.1016/j.drudis.2017.04.012. PMID   28458043.
  26. ↑ Krátký M, Vinšová J (Dec 2012). "Advances in mycobacterial isocitrate lyase targeting and inhibitors". Current Medicinal Chemistry. 19 (36): 6126–37. doi:10.2174/0929867311209066126. PMID   23092127.
  27. ↑ Lee YV, Wahab HA, Choong YS (2015). "Potential inhibitors for isocitrate lyase of Mycobacterium tuberculosis and non-M. tuberculosis: a summary". BioMed Research International. 2015: 895453. doi: 10.1155/2015/895453 . PMC   4306415 . PMID   25649791.

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