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69  structures 1846  species 1  interaction 4174  sequences 13  architectures

Family: ICL (PF00463)

Summary: Isocitrate lyase family

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This is the Wikipedia entry entitled "Isocitrate lyase". More...

Isocitrate lyase Edit Wikipedia article

Isocitrate Lyase
Isocitrate lyase.png
Homotetrameric structure of Isocitrate lyase from E. coli. Based on PDB 1IGW.[1]
Identifiers
EC number 4.1.3.1
CAS number 9045-78-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Isocitrate lyase family
Identifiers
Symbol ICL
Pfam PF00463
InterPro IPR000918
PROSITE PDOC00145
SCOP 1f8m
SUPERFAMILY 1f8m

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]

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[edit]

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 reaction

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[edit]

As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1DQU, 1F61, 1F8I, 1F8M, and 1IGW.

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.

Biological Function[edit]

The ICL enzyme has been found to be functional in various archaea, bacteria, protists, plants, fungi, and nematodes.[9] Although the gene has been found in genomes of nematodes and cnidaria, it has not been found in the genomes of placental mammals.[9]

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.[10] Thus, while the TCA cycle yields no net carbon assimilation, the glyoxylate cycle generates intermediates that can be used to synthesize glucose (via gluconeogenesis), and other biosynthetic products. As a result, organisms that use ICL and malate synthase are able to synthesize glucose and 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 which use oilseeds. In these germinating seeds, the breakdown of oils generates acetyl-CoA. This serves as a substrate for the glyoxylate cycle, which generates other cyclic intermediates and serves as a primary nutrient source prior to the production of sugars from photosynthesis.[8]

Disease Relevance[edit]

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.[11]

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.[12][13] In this latter case, ICL has been found to be essential for survival in the host.[14]

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] More research is needed to identify inhibitors that selectively target enzymes in the glyoxylate cycle.

See also[edit]

References[edit]

  1. ^ Britton, KL; Abeysinghe IS, Baker PJ, Barynin V, Diehl P, Langridge SJ, McFadden BA, Sedelnikova SE, Stillman TJ, Weeradechapon K, Rice DW (Sep 2001). "The structure and domain organization of Escherichia coli isocitrate lyase". Acta Crystallogr D 57 (9): 1209–1218. doi:10.1107/S0907444901008642. PMID 11526312. 
  2. ^ Beeching JR (1989). "High sequence conservation between isocitrate lyase from Escherichia coli and Ricinus communis". Protein Seq. Data Anal. 2 (6): 463–466. PMID 2696959. 
  3. ^ Tanaka A, Atomi H, Ueda M, Hikida M, Hishida T, Teranishi Y (1990). "Peroxisomal isocitrate lyase of the n-alkane-assimilating yeast Candida tropicalis: gene analysis and characterization". J. Biochem. 107 (2): 262–266. PMID 2361956. 
  4. ^ a b c d e f g h i Dunn, MF; Ramirez-Trujill JA, Hernandez-Lucas I (Oct 2009). "Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis". Microbiology 155 (10): 3166–3175. doi:10.1099/mic.0.030858-0. PMID 19684068. 
  5. ^ Garrett R and Grisham CN (2008). Biochemistry. Brooks Cole. p. 588. ISBN 978-0-495-10935-8. 
  6. ^ a b Cozzone, AJ (1998). "Regulation of acetate metabolism by protein phosphorylation in enteric bacteria". Annu. Rev. Microbiol. 52: 127–164. doi:10.1146/annurev.micro.52.1.127. PMID 9891796. 
  7. ^ Rehman, A; McFadden BA (Jul 1997). "Lysine 194 is functional in isocitrate lyase from Escherichia coli". Curr. Microbiol. 35 (1): 14–17. doi:10.1007/s002849900203. PMID 9175553. 
  8. ^ a b Eastmond, PJ; Graham IA (Feb 2001). "Re-examining the role of the glyoxylate cycle in oilseeds". Trends Plant Sci 6 (2): 72–78. doi:10.1016/S1360-1385(00)01835-5. PMID 11173291. 
  9. ^ a b Kondrashov, FA; Koonin EV, Morgunov IG, Finogenova TV, Kondrashova MN (23 Oct 2006). "Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation". Biol Direct 1 (31): 31. doi:10.1186/1745-6150-1-31. PMC 1630690. PMID 17059607. 
  10. ^ Kornberg, HL; Krebs HA (18 May 1957). "Synthesis of cell constituents from C2-units by a modified tricarboxylic acid cycle". Nature 179 (4568): 988–991. doi:10.1038/179988a0. PMID 13430766. 
  11. ^ Idnurm, A; Howlett BJ (Oct 2002). "Isocitrate lyase is essential for pathogenicity of the fungus Leptosphaeria maculans to canola (Brassica napus)". Eukaryot Cell 1 (5): 719–724. doi:10.1128/EC.1.5.719-724.2002. PMC 126752. PMID 12455691. 
  12. ^ Lorenz, MC; Bender JA (Oct 2004). "Fink GR". Eukaryot Cell 3 (5): 1076–1087. doi:10.1128/EC.3.5.1076-1087.2004. PMC 522606. PMID 15470236. 
  13. ^ Srivastava, V; Jain A, Srivastava BS, Srivastava R (May 2008). "Selection of genes of Mycobacterium tuberculosis upregulated during residence in lungs of infected mice". Tuberculosis (Edinb) 88 (3): 171–177. doi:10.1016/j.tube.2007.10.002. PMID 18054522. 
  14. ^ Muñoz-Elías, EJ; McKinney JD (Jun 2005). "Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence". Nat Med 11 (6): 638–644. doi:10.1038/nm1252. PMC 1464426. PMID 15895072. 

Further reading[edit]

  • McFadden BA and Howes WV (1963). "Crystallisation and some properties of isocitrate lyase from Pseudomonas indigofera". J. Biol. Chem. 238: 1737–1742. 
  • Shiio I, Shiio T and McFadden BA (1965). "Isocitrate lyase from Pseudomonas indigofera. I. Preparation, amino acid composition and molecular weight". Biochim. Biophys. Acta 96: 114–22. PMID 14285253. 
  • VICKERY HB (1962). "A suggested new nomenclature for the isomers of isocitric acid". J. Biol. Chem. 237: 1739–41. PMID 13925783. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Isocitrate lyase family". More...

Isocitrate lyase family Edit Wikipedia article

Isocitrate lyase family
Identifiers
Symbol ICL
Pfam PF00463
InterPro IPR000918
PROSITE PDOC00145
SCOP 1f8m
SUPERFAMILY 1f8m
CDD cd00377

Isocitrate lyase family is a family of evolutionarily related proteins.

Isocitrate lyase (EC 4.1.3.1)[1][2] is an enzyme that catalyzes the conversion of isocitrate to succinate and glyoxylate. This is the first step in the glyoxylate bypass, an alternative to the tricarboxylic acid cycle in bacteria, fungi and plants. A cysteine, a histidine and a glutamate or aspartate have been found to be important for the enzyme's catalytic activity. 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.

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 antiobiotics.

[edit] Subfamilies

[edit] References

  1. ^ Beeching JR (1989). "High sequence conservation between isocitrate lyase from Escherichia coli and Ricinus communis". Protein Seq. Data Anal. 2 (6): 463–466. PMID 2696959. 
  2. ^ Tanaka A, Atomi H, Ueda M, Hikida M, Hishida T, Teranishi Y (1990). "Peroxisomal isocitrate lyase of the n-alkane-assimilating yeast Candida tropicalis: gene analysis and characterization". J. Biochem. 107 (2): 262–266. PMID 2361956. 

This article incorporates text from the public domain Pfam and InterPro IPR000918

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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This tab holds annotation information from the InterPro database.

InterPro entry IPR000918

Isocitrate lyase (EC) [PUBMED:2696959, PUBMED:2361956] is an enzyme that catalyzes the conversion of isocitrate to succinate and glyoxylate. This is the first step in the glyoxylate bypass, an alternative to the tricarboxylic acid cycle in bacteria, fungi and plants. A cysteine, a histidine and a glutamate or aspartate have been found to be important for the enzyme's catalytic activity. 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.

Other enzymes also belong to this family including carboxyvinyl-carboxyphosphonate phosphorylmutase (EC) which catalyses the conversion of 1-carboxyvinyl carboxyphosphonate to 3-(hydrohydroxyphosphoryl) pyruvate carbon dioxide, and phosphoenolpyruvate mutase (EC), which is involved in the biosynthesis of phosphinothricin tripeptide antiobiotics.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan PK_TIM (CL0151), which has the following description:

This superfamily consists of a number of TIM barrel domains found in enzymes such as pyruvate kinase, malate synthase and citrate lyase.

The clan contains the following 10 members:

C-C_Bond_Lyase HpcH_HpaI ICL Malate_synthase Pantoate_transf PEP-utilizers_C PEP_mutase PEPcase PEPcase_2 PK

Alignments

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(4281)
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(663)
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  Seed
(7)
Full
(4174)
Representative proteomes NCBI
(4424)
Meta
(4281)
RP15
(314)
RP35
(663)
RP55
(947)
RP75
(1148)
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  Seed
(7)
Full
(4174)
Representative proteomes NCBI
(4424)
Meta
(4281)
RP15
(314)
RP35
(663)
RP55
(947)
RP75
(1148)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

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Curation and family details

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Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 7
Number in full: 4174
Average length of the domain: 225.10 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 93.61 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 19.5 19.5
Trusted cut-off 19.5 19.5
Noise cut-off 19.4 19.3
Model length: 526
Family (HMM) version: 16
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Species distribution

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Interactions

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ICL

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the ICL domain has been found. There are 69 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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