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Maleylacetoacetate isomerase

January 01, 1970

In enzymology, maleylacetoacetate isomerase (EC 5.2.1.2) is an enzyme that catalyzes the chemical reaction

Maleylacetoacetate Isomerase
This represents the surface structure of the enzyme.
Identifiers
EC no.5.2.1.2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
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4-maleylacetoacetate 4-fumarylacetoacetate

This enzyme belongs to the family of isomerases, specifically cis-trans isomerases. The systematic name of this enzyme class is 4-maleylacetoacetate cis-trans-isomerase.

4-Maleylacetoacetate isomerase is an enzyme involved in the degradation of L-phenylalanine. It is encoded by the gene glutathione S-transferase zeta 1, or GSTZ1. This enzyme catalyzes the conversion of 4-maleylacetoacetate to 4-fumarylacetoacetate. 4-Maleylacetoacetate isomerase belongs to the zeta class of the glutathione S-transferase (GST) superfamily.[1]

This image shows the structure of the peptide backbone of 4-maleylacetoacetate isomerase, highlighting the glutathione binding site.

Mechanism edit

In the  phenylalanine degradation pathway, 4-maleylacetoacetate isomerase catalyzes a cis-trans isomerization of  4-maleylacetoacetate to fumarylacetoacetate. 4-maleylacetoacetate isomerase requires the cofactor glutathione to function.[1] Ser 15, Cys 16, Gln 111, and the helix dipole of alpha 1 of the enzyme stabilize the thiolate form of glutathione which activates it to attack the alpha carbon of 4-maleylacetoacetate, thus breaking the double bond and allowing rotation around the single bond.[1]

 
This image shows the conversion of 4-maleylacetoacetate to fumarate and acetoacetate, as well as the enzymes that catalyze each step and cofactors required.

4-maleylacetoacetate is converted to 4-fumarylacetoacetate, this compound can be broken down into fumarate and acetoacetate by the enzyme fumarylacetoacetate hydrolase.[2]

The conversion of 4-maleylacetoacetate to fumarylacetoacetate is a step in the catabolism of phenylalanine and tyrosine, amino acids acquired through dietary protein consumption. When 4-maleylacetoacetate isomerase is unable to function properly, the 4-maleylacetoacetate may be converted instead to succinylacetoacetate and further broken down into succinate and acetoacetate by fumarylacetoacetate hydrolase.[3]

 
This image shows the pathway that 4-maleylacetoacetate follows when 4-maleylacetoacetate isomerase is not present.

Structure edit

 
This image shows the folding patterns, as well as both the N- and C-terminals of the enzyme 4-maleylacetoacetate isomerase.

4-maleylacetoacetate is a homodimer. It is classified as an isomerase transferase. It has a total residue count of 216 and a total atom count of 1700. This enzyme's theoretical weight is 24.11 KDa.[1] 4-maleylacetoacetate isomerase has 3 isoforms[4] The most common isoform has two domains, the N-terminal domain (4-87) the C terminal domain (92-212) and the glutathione binding site (14-19, 71-72 and 115-117).  The N-terminal domain has a four stranded beta sheet which is sandwiched by alpha helices on both sides to form a three layer sandwich tertiary structure. The C terminal domain is composed mostly of alpha helices and has an up down structure of tightly bundled alpha helices.[1]

Glutathione binds in positions 14-19, 71-72, and 115-117. It also binds the sulfate ion and dithiothreitol.[3]

Clinical significance edit

Maleylacetoacetate isomerase deficiency is a disease caused by a mutation in the gene GSTZ1.

This is an autosomal recessive inborn error of metabolism. It is caused by a mutation in the gene that codes for the synthesis of 4-maleylacetoacetate isomerase, GSTZ1.

Mutations in 4-maleylacetoacetate isomerase resulted in accumulation of fumarylacetoacetate and succinylacetone in the urine, but individuals were otherwise healthy. It is likely that there exists an alternate nonenzymatic bypass that allows the catabolism of 4-maleylacetoacetate in the absence of 4-maleylacetoacetate isomerase. Because of this mechanism, a mutation in the gene encoding 4-Maleylacetoacetate isomerase is not considered dangerous.[5]

GSTZ1 is highly expressed in the liver, however mutations in this gene do not impair liver function or coagulation.[6]

Gene expression edit

The gene from which this enzyme is synthesized is mostly expressed in the liver, with some expression in the kidneys, skeletal muscle, and brain. It is also expressed in melanocytes, synovium, placenta, breasts, fetal liver and heart.[6]

 
This graph shows where the gene that encodes 4-maleylacetoactetate isomerase is most highly expressed.

Related enzymes edit

Other enzymes involved in the catabolism of phenylalanine include phenylalanine hydroxylase, aminotransferase, p-hydroxyphenylpyruvate dioxygenase, homogentisate oxidase, and fumarylacetoacetate hydrolase. Mutations in some of these enzymes can lead to more severe diseases such as, phenylketonuria, alkaptonuria, and tyrosinemia.

The gene GSTZ1 is located on chromosome 14q24.3.[7]

References edit

  1. ^ a b c d e PDB: 1FW1​; Polekhina G, Board PG, Blackburn AC, Parker MW (February 2001). "Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity". Biochemistry. 40 (6): 1567–76. doi:10.1021/bi002249z. PMID 11327815.
  2. ^ Arias-Barrau E, Olivera ER, Luengo JM, Fernández C, Galán B, García JL, Díaz E, Miñambres B (August 2004). "The homogentisate pathway: a central catabolic pathway involved in the degradation of L-phenylalanine, L-tyrosine, and 3-hydroxyphenylacetate in Pseudomonas putida". Journal of Bacteriology. 186 (15): 5062–77. doi:10.1128/JB.186.15.5062-5077.2004. PMC 451635. PMID 15262943.
  3. ^ a b Fernández-Cañón JM, Baetscher MW, Finegold M, Burlingame T, Gibson KM, Grompe M (July 2002). "Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism". Molecular and Cellular Biology. 22 (13): 4943–51. doi:10.1128/MCB.22.13.4943-4951.2002. PMC 133921. PMID 12052898.
  4. ^ Universal protein resource accession number GSTZ1 for "Maleylacetoacetate isomerase" at UniProt.
  5. ^ Lim CE, Matthaei KI, Blackburn AC, Davis RP, Dahlstrom JE, Koina ME, Anders MW, Board PG (August 2004). "Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases". The American Journal of Pathology. 165 (2): 679–93. doi:10.1016/S0002-9440(10)63332-9. PMC 1618558. PMID 15277241.
  6. ^ a b "GSTZ1 glutathione S-transferase zeta 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-12-06.
  7. ^ "Symbol report for GSTZ1". www.genenames.org.

Further reading edit

  • "3,5-Dioxooctanedioic acid". PubChem Compound Database. National Center for Biotechnology Information. U.S. National Library of Medicine.
  • Blackburn AC, Woollatt E, Sutherland GR, Board PG (1998). "Characterization and chromosome location of the gene GSTZ1 encoding the human Zeta class glutathione transferase and maleylacetoacetate isomerase". Cytogenetics and Cell Genetics. 83 (1–2): 109–14. doi:10.1159/000015145. PMID 9925947. S2CID 22835884.
  • Universal protein resource accession number O43708 for "Maleylacetoacetate isomerase" at UniProt.
  • "Glutathione". PubChem Compound Database. National Center for Biotechnology Information. U.S. National Library of Medicine.

January 01, 1970
maleylacetoacetate, isomerase, enzymology, maleylacetoacetate, isomerase, enzyme, that, catalyzes, chemical, reactionmaleylacetoacetate, isomerasethis, represents, surface, structure, enzyme, identifiersec, 2databasesintenzintenz, viewbrendabrenda, entryexpasy. In enzymology maleylacetoacetate isomerase EC 5 2 1 2 is an enzyme that catalyzes the chemical reactionMaleylacetoacetate IsomeraseThis represents the surface structure of the enzyme IdentifiersEC no 5 2 1 2DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteins 4 maleylacetoacetate displaystyle rightleftharpoons 4 fumarylacetoacetate This enzyme belongs to the family of isomerases specifically cis trans isomerases The systematic name of this enzyme class is 4 maleylacetoacetate cis trans isomerase 4 Maleylacetoacetate isomerase is an enzyme involved in the degradation of L phenylalanine It is encoded by the gene glutathione S transferase zeta 1 or GSTZ1 This enzyme catalyzes the conversion of 4 maleylacetoacetate to 4 fumarylacetoacetate 4 Maleylacetoacetate isomerase belongs to the zeta class of the glutathione S transferase GST superfamily 1 This image shows the structure of the peptide backbone of 4 maleylacetoacetate isomerase highlighting the glutathione binding site Contents 1 Mechanism 2 Structure 3 Clinical significance 4 Gene expression 5 Related enzymes 6 References 7 Further readingMechanism editIn the phenylalanine degradation pathway 4 maleylacetoacetate isomerase catalyzes a cis trans isomerization of 4 maleylacetoacetate to fumarylacetoacetate 4 maleylacetoacetate isomerase requires the cofactor glutathione to function 1 Ser 15 Cys 16 Gln 111 and the helix dipole of alpha 1 of the enzyme stabilize the thiolate form of glutathione which activates it to attack the alpha carbon of 4 maleylacetoacetate thus breaking the double bond and allowing rotation around the single bond 1 nbsp This image shows the conversion of 4 maleylacetoacetate to fumarate and acetoacetate as well as the enzymes that catalyze each step and cofactors required 4 maleylacetoacetate is converted to 4 fumarylacetoacetate this compound can be broken down into fumarate and acetoacetate by the enzyme fumarylacetoacetate hydrolase 2 The conversion of 4 maleylacetoacetate to fumarylacetoacetate is a step in the catabolism of phenylalanine and tyrosine amino acids acquired through dietary protein consumption When 4 maleylacetoacetate isomerase is unable to function properly the 4 maleylacetoacetate may be converted instead to succinylacetoacetate and further broken down into succinate and acetoacetate by fumarylacetoacetate hydrolase 3 nbsp This image shows the pathway that 4 maleylacetoacetate follows when 4 maleylacetoacetate isomerase is not present Structure edit nbsp This image shows the folding patterns as well as both the N and C terminals of the enzyme 4 maleylacetoacetate isomerase 4 maleylacetoacetate is a homodimer It is classified as an isomerase transferase It has a total residue count of 216 and a total atom count of 1700 This enzyme s theoretical weight is 24 11 KDa 1 4 maleylacetoacetate isomerase has 3 isoforms 4 The most common isoform has two domains the N terminal domain 4 87 the C terminal domain 92 212 and the glutathione binding site 14 19 71 72 and 115 117 The N terminal domain has a four stranded beta sheet which is sandwiched by alpha helices on both sides to form a three layer sandwich tertiary structure The C terminal domain is composed mostly of alpha helices and has an up down structure of tightly bundled alpha helices 1 Glutathione binds in positions 14 19 71 72 and 115 117 It also binds the sulfate ion and dithiothreitol 3 Clinical significance editMaleylacetoacetate isomerase deficiency is a disease caused by a mutation in the gene GSTZ1 This is an autosomal recessive inborn error of metabolism It is caused by a mutation in the gene that codes for the synthesis of 4 maleylacetoacetate isomerase GSTZ1 Mutations in 4 maleylacetoacetate isomerase resulted in accumulation of fumarylacetoacetate and succinylacetone in the urine but individuals were otherwise healthy It is likely that there exists an alternate nonenzymatic bypass that allows the catabolism of 4 maleylacetoacetate in the absence of 4 maleylacetoacetate isomerase Because of this mechanism a mutation in the gene encoding 4 Maleylacetoacetate isomerase is not considered dangerous 5 GSTZ1 is highly expressed in the liver however mutations in this gene do not impair liver function or coagulation 6 Gene expression editThe gene from which this enzyme is synthesized is mostly expressed in the liver with some expression in the kidneys skeletal muscle and brain It is also expressed in melanocytes synovium placenta breasts fetal liver and heart 6 nbsp This graph shows where the gene that encodes 4 maleylacetoactetate isomerase is most highly expressed Related enzymes editOther enzymes involved in the catabolism of phenylalanine include phenylalanine hydroxylase aminotransferase p hydroxyphenylpyruvate dioxygenase homogentisate oxidase and fumarylacetoacetate hydrolase Mutations in some of these enzymes can lead to more severe diseases such as phenylketonuria alkaptonuria and tyrosinemia The gene GSTZ1 is located on chromosome 14q24 3 7 References edit a b c d e PDB 1FW1 Polekhina G Board PG Blackburn AC Parker MW February 2001 Crystal structure of maleylacetoacetate isomerase glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity Biochemistry 40 6 1567 76 doi 10 1021 bi002249z PMID 11327815 Arias Barrau E Olivera ER Luengo JM Fernandez C Galan B Garcia JL Diaz E Minambres B August 2004 The homogentisate pathway a central catabolic pathway involved in the degradation of L phenylalanine L tyrosine and 3 hydroxyphenylacetate in Pseudomonas putida Journal of Bacteriology 186 15 5062 77 doi 10 1128 JB 186 15 5062 5077 2004 PMC 451635 PMID 15262943 a b Fernandez Canon JM Baetscher MW Finegold M Burlingame T Gibson KM Grompe M July 2002 Maleylacetoacetate isomerase MAAI GSTZ deficient mice reveal a glutathione dependent nonenzymatic bypass in tyrosine catabolism Molecular and Cellular Biology 22 13 4943 51 doi 10 1128 MCB 22 13 4943 4951 2002 PMC 133921 PMID 12052898 Universal protein resource accession number GSTZ1 for Maleylacetoacetate isomerase at UniProt Lim CE Matthaei KI Blackburn AC Davis RP Dahlstrom JE Koina ME Anders MW Board PG August 2004 Mice deficient in glutathione transferase zeta maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha mu and pi class glutathione transferases The American Journal of Pathology 165 2 679 93 doi 10 1016 S0002 9440 10 63332 9 PMC 1618558 PMID 15277241 a b GSTZ1 glutathione S transferase zeta 1 Homo sapiens human Gene NCBI www ncbi nlm nih gov Retrieved 2018 12 06 Symbol report for GSTZ1 www genenames org Further reading edit 3 5 Dioxooctanedioic acid PubChem Compound Database National Center for Biotechnology Information U S National Library of Medicine Blackburn AC Woollatt E Sutherland GR Board PG 1998 Characterization and chromosome location of the gene GSTZ1 encoding the human Zeta class glutathione transferase and maleylacetoacetate isomerase Cytogenetics and Cell Genetics 83 1 2 109 14 doi 10 1159 000015145 PMID 9925947 S2CID 22835884 Universal protein resource accession number O43708 for Maleylacetoacetate isomerase at UniProt Glutathione PubChem Compound Database National Center for Biotechnology Information U S National Library of Medicine Portal nbsp Biology Retrieved from https en wikipedia org w index php title Maleylacetoacetate isomerase amp oldid 1165187806, wikipedia, wiki, book, books, library,

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