Maleate isomerase

In enzymology, a maleate isomerase (EC 5.2.1.1), or maleate cis-tran isomerase, is a member of the Asp/Glu racemase superfamily discovered in bacteria. It is responsible for catalyzing cis-trans isomerization of the C2-C3 double bond in maleate to produce fumarate,[1] which is a critical intermediate in citric acid cycle.[2] The presence of an exogenous mercaptan is required for catalysis to happen.[3]

Illustration of the overall isomerization catalyzed by maleate isomerase
Maleate Isomerase
Maleate isomerase from Pseudomonas putida
Identifiers
EC no.5.2.1.1
CAS no.9023-74-9
Databases
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MetaCycmetabolic pathway
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Maleate isomerase participates in butanoate metabolism and nicotinate and nicotinamide metabolism.[4] It is an essential enzyme for the last step of metabolic degradation pathway of nicotinic acid. Recently, maleate isomerase has been an industrial target for degradation of tobacco waste.[5][6] It is also got attention for its involvement in aspartic acid and maleic acid production.[7][8][9]

Maleate isomerase has been utilized by multiple bacteria species, including Pseudomonas fluorescens,[3] Alcaligenes faecalis,[10] Bacillus stearothermophilus,[11] Serratia marcescens[8], Pseudomonas putida[12] and Nocardia farcinica.[1][5] The enzyme has a molecular weight of 74,000 and a turnover number of 1,800 moles per mole of protein per min.[3]

Structure

Analogous to other Asp/Glu racemase members, maleate isomerase is formed by two identical protomers, with a flat dimerization surface.[13][14] Each protomer of maleate isomerase has two domains connected by a pseudo-twofold symmetry, with each domain contributes one catalytic cysteine, which is crucial to the isomerase activity at the active site.[5] Experiment shows that substitution of either cysteine by serine significantly reduces the rate of reaction of the enzyme.[1]

In addition to catalytic cysteines, a few other residues at the active site are important for the recognition of the substrate and help stabilize reaction intermediates.[5][1] For example, maleate isomerase from Pseudomonas putida S16 uses Asn17 and Asn169 form hydrogen bonds with the carboxylate group of the maleate distal to Cys82.[5] Tyr139 hydrogen bonds with the carboxylate group of the maleate proximal to Cys82.[5] Pro14 and Val84 make van der Waals interactions with the C2 and C3 carbon atoms of the maleate.[5]

Mechanism

The mechanism of maleate isomerase is considered to be similar to other Asp/Glu racemase members, though have not been fully understood. One proposed reaction mechanism of Nocardia farcinia maleate isomerase is as follows.[1][9] At the active site of maleate isomerase, Cys76 is first deprotonated to be more readily act as a nucleophile.[1] The sulfur atom of the deprotonated Cys76 then carries a direct nucleophilic attack to the C2 atom of the maleate, covalently bonding to the C2 atom.[9][1] Concomitantly, thiol proton of Cys194 is transferred onto the C3 atom of the maleate to form a succinyl-cysteine intermediate.[9][1] The newly formed C2–C3 single bond is then rotated, with Cys76S–C2 bond dissociated, and C3 atom of the maleate deprotonated by Cys194, thus forming fumarate with regeneration of a neutral Cys194.[9][1] In certain type of bacteria, maleate seems completely buried inside the cavity of maleate isomerase and cannot be seen on the surface of the enzyme.[5]

One proposed reaction mechanism of maleate isomerase (C1, C2, C3, C4 are the four carbon atoms in maleate from top to bottom)

Industrial relevance

Maleate isomerase can be used to produce fumaric acid, an important building block material for polymerization and esterification reactions, from the isomerization of maleic acid.[7] Maleic acid is produced from maleic anhydride.[7]

Maleic acid can also be converted into fumaric acid by thermal or catalytic cis–trans isomerization.[15][16] However, these conversion methods are occurring at high temperatures that causes formation of by-products from maleic and fumaric acids, as a result, yields are below the equilibrium yields.[17] This problem was the main motivation for the alternative enzymatic strategy with maleate isomerase that would facilitate isomerization without by-products.[7]

It is known that, even at moderate temperatures, natural maleate isomerase is unstable.[18] For that reason, heat-stable maleate isomerases are engineered and applied.[7] For example, thermo-stable maleate isomerases derived from Bacillus stearothermophilus, Bacillus brevis, and Bacillus sporothermodurans were used to improve the process.[7][17] In a study using Pseudomonas alcaligenes XD-1, conversion rate from maleic acid into fumaric acid could be achieved as high as 95%.[19][20][7]

References
  1. Fisch F, Fleites CM, Delenne M, Baudendistel N, Hauer B, Turkenburg JP, Hart S, Bruce NC, Grogan G (August 2010). "A covalent succinylcysteine-like intermediate in the enzyme-catalyzed transformation of maleate to fumarate by maleate isomerase". Journal of the American Chemical Society. 132 (33): 11455–7. doi:10.1021/ja1053576. PMID 20677745.
  2. Tanaka K, Kobayashi K, Ogasawara N (September 2003). "The Bacillus subtilis YufLM two-component system regulates the expression of the malate transporters MaeN (YufR) and YflS, and is essential for utilization of malate in minimal medium". Microbiology. 149 (Pt 9): 2317–29. doi:10.1099/mic.0.26257-0. PMID 12949159.
  3. Scher W, Jakoby WB (April 1969). "Maleate isomerase". The Journal of Biological Chemistry. 244 (7): 1878–82. doi:10.1016/S0021-9258(18)91762-X. PMID 5780844.
  4. Behrman EJ, Stanier RY (October 1957). "The bacterial oxidation of nicotinic acid". The Journal of Biological Chemistry. 228 (2): 923–45. doi:10.1016/S0021-9258(18)70671-6. PMID 13475371.
  5. Chen D, Tang H, Lv Y, Zhang Z, Shen K, Lin K, Zhao YL, Wu G, Xu P (March 2013). "Structural and computational studies of the maleate isomerase from Pseudomonas putida S16 reveal a breathing motion wrapping the substrate inside". Molecular Microbiology. 87 (6): 1237–44. doi:10.1111/mmi.12163. PMID 23347155. S2CID 13313674.
  6. Tang H, Yao Y, Wang L, Yu H, Ren Y, Wu G, Xu P (2012). "Genomic analysis of Pseudomonas putida: genes in a genome island are crucial for nicotine degradation". Scientific Reports. 2: 377. doi:10.1038/srep00377. PMC 3332521. PMID 22530095.
  7. Roa Engel CA, Straathof AJ, Zijlmans TW, van Gulik WM, van der Wielen LA (March 2008). "Fumaric acid production by fermentation". Applied Microbiology and Biotechnology. 78 (3): 379–89. doi:10.1007/s00253-007-1341-x. PMC 2243254. PMID 18214471.
  8. Hatakeyama K, Goto M, Kobayashi M, Terasawa M, Yukawa H (July 2000). "Analysis of oxidation sensitivity of maleate cis-trans isomerase from Serratia marcescens". Bioscience, Biotechnology, and Biochemistry. 64 (7): 1477–85. doi:10.1271/bbb.64.1477. PMID 10945267.
  9. Dokainish HM, Ion BF, Gauld JW (June 2014). "Computational investigations on the catalytic mechanism of maleate isomerase: the role of the active site cysteine residues". Physical Chemistry Chemical Physics. 16 (24): 12462–74. doi:10.1039/c4cp01342e. PMID 24827730.
  10. Hatakeyama K, Asai Y, Uchida Y, Kobayashi M, Terasawa M, Yukawa H (October 1997). "Gene cloning and characterization of maleate cis-trans isomerase from Alcaligenes faecalis". Biochemical and Biophysical Research Communications. 239 (1): 74–9. doi:10.1006/bbrc.1997.7430. PMID 9345272.
  11. Hatakeyama K, Goto M, Uchida Y, Kobayashi M, Terasawa M, Yukawa H (March 2000). "Molecular analysis of maleate cis-trans isomerase from thermophilic bacteria". Bioscience, Biotechnology, and Biochemistry. 64 (3): 569–76. doi:10.1271/bbb.64.569. PMID 10803955. S2CID 43798064.
  12. Jiménez JI, Canales A, Jiménez-Barbero J, Ginalski K, Rychlewski L, García JL, Díaz E (August 2008). "Deciphering the genetic determinants for aerobic nicotinic acid degradation: the nic cluster from Pseudomonas putida KT2440". Proceedings of the National Academy of Sciences of the United States of America. 105 (32): 11329–34. doi:10.1073/pnas.0802273105. PMC 2516282. PMID 18678916.
  13. Ruzheinikov SN, Taal MA, Sedelnikova SE, Baker PJ, Rice DW (November 2005). "Substrate-induced conformational changes in Bacillus subtilis glutamate racemase and their implications for drug discovery". Structure. 13 (11): 1707–13. doi:10.1016/j.str.2005.07.024. PMID 16271894.
  14. Ohtaki A, Nakano Y, Iizuka R, Arakawa T, Yamada K, Odaka M, Yohda M (March 2008). "Structure of aspartate racemase complexed with a dual substrate analogue, citric acid, and implications for the reaction mechanism". Proteins. 70 (4): 1167–74. doi:10.1002/prot.21528. PMID 17847084. S2CID 38854552.
  15. Lohbeck K, Haferkorn H, Fuhrmann W, Fedtke N (2000). Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA. doi:10.1002/14356007.a16_053. ISBN 978-3-527-30673-2.
  16. Otsuka K (January 1961). "Cis-trans Isomerase Isomerisation from Maleic Acid to Fumaric Acid". Agricultural and Biological Chemistry. 25 (9): 726–730. doi:10.1271/bbb1961.25.726.
  17. Goto M, Nara T, Tokumaru I, Fugono N, Uchida Y, Terasawa M (February 1997). "Method of producing fumaric acid". {{cite journal}}: Cite journal requires |journal= (help)
  18. Takamura Y, Takamura T, Soejima M, Uemura T (January 1969). "Studies on the Induced Synthesis of Maleate Cis-Trans Isomerase by Malonate: Part III. Purification and Properties of Maleate cis-trans Isomerase Induced by Malonate". Journal Agricultural and Biological Chemistry. 33 (5): 718–728. doi:10.1080/00021369.1969.10859369.
  19. Nakajima-Kambe, Toshiaki; Nozue, Takehiro; Mukouyama, Masaharu; Nakahara, Tadaatsu (January 1997). "Bioconversion of maleic acid to fumaric acid by Pseudomonas alcaligenes strain XD-1". Journal of Fermentation and Bioengineering. 84 (2): 165–168. doi:10.1016/S0922-338X(97)82549-4.
  20. Ichikawa, Sosaku; Iino, Tomoko; Sato, Seigo; Nakahara, Tadaatsu; Mukataka, Sukekuni (January 2003). "Improvement of production rate and yield of fumaric acid from maleic acid by heat treatment of Pseudomonas alcaligenes strain XD-1". Biochemical Engineering Journal. 13 (1): 7–13. doi:10.1016/S1369-703X(02)00080-3.
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