Dihydroneopterin aldolase
| dihydroneopterin aldolase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 oktamer | |||||||||
| Identifiers | |||||||||
| EC no. | 4.1.2.25 | ||||||||
| CAS no. | 37290-59-8 | ||||||||
| 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 / QuickGO | ||||||||
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| Dihydroneopterin aldolase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 crystal structure of 7,8-dihydroneopterin aldolase in complex with guanine | |||||||||
| Identifiers | |||||||||
| Symbol | FolB | ||||||||
| Pfam | PF02152 | ||||||||
| Pfam clan | CL0334 | ||||||||
| InterPro | IPR006157 | ||||||||
| SCOP2 | 1b9l / SCOPe / SUPFAM | ||||||||
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The enzyme dihydroneopterin aldolase (EC 4.1.2.25) catalyzes the chemical reaction
- 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8- dihydropteridine 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + glycolaldehyde
This enzyme belongs to the family of lyases, specifically the aldehyde-lyases, which cleave carbon-carbon bonds. The systematic name of this enzyme class is 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropt eridine glycolaldehyde-lyase (2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine-forming). Other names in common use include 2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-, and dihydropteridine glycolaldehyde-lyase. This enzyme participates in folate biosynthesis.
Structural studies
[edit]The structural studies of DHNA have greatly advanced our understanding of its catalytic mechanism, revealing the roles of conserved amino acids in substrate binding and enzymatic activity.[1] Comparative analyses of bacterial DHNA enzymes have uncovered differences in their active site architectures, providing valuable information for the design of species-specific inhibitors.[2] These findings underscore the potential of targeting DHNA as a strategy to disrupt folate biosynthesis in pathogenic bacteria, as demonstrated by the successful inhibition of Staphylococcus aureus and Mycobacterium tuberculosis DHNA in vitro.[3] The absence of DHNA in mammalian cells enhances the selectivity and therapeutic potential of DHNA-specific antimicrobial agents, reducing the likelihood of off-target effects.[4]
Furthermore, the study of bifunctional DHNA-HPPK enzymes, such as those found in Streptococcus pneumoniae, has illuminated the interplay between folate pathway enzymes, offering additional targets for antimicrobial drug development.[5] The development of potent DHNA inhibitors has been a promising step toward novel antibacterial therapies, with some compounds achieving nanomolar-level efficacy in vitro.[3] However, the lack of structural data for Helicobacter pylori DHNA remains a significant gap, emphasizing the need for future research to facilitate the development of narrow-spectrum antibiotics tailored to specific infections.[3]
Structural studies
[edit]As of late 2007, 13 structures have been solved for this class of enzymes, with PDB accession codes 1NBU, 1RRI, 1RRW, 1RRY, 1RS2, 1RS4, 1RSD, 1RSI, 1U68, 1Z9W, 2CG8, 2NM2, and 2NM3.
References
[edit]- ^ Hoh, F.; Yang, Y. S.; Guignard, L.; Padilla, A.; Stern, M. H.; Lhoste, J. M.; van Tilbeurgh, H. (1998-02-15). "Crystal structure of p14TCL1, an oncogene product involved in T-cell prolymphocytic leukemia, reveals a novel beta-barrel topology". Structure (London, England: 1993). 6 (2): 147–155. doi:10.1016/s0969-2126(98)00017-3. ISSN 0969-2126. PMID 9519406.
- ^ Mandimika, Tafadzwa; Baykus, Hakan; Vissers, Yvonne; Jeurink, Prescilla; Poortman, Jenneke; Garza, Cutberto; Kuiper, Harry; Peijnenburg, Ad (2007-11-28). "Differential gene expression in intestinal epithelial cells induced by single and mixtures of potato glycoalkaloids". Journal of Agricultural and Food Chemistry. 55 (24): 10055–10066. Bibcode:2007JAFC...5510055M. doi:10.1021/jf0724320. ISSN 0021-8561. PMID 17973450.
- ^ a b c Li, James J.; Chao, Hann-Guang; Wang, Haixia; Tino, Joseph A.; Lawrence, R. Michael; Ewing, William R.; Ma, Zhengping; Yan, Mujing; Slusarchyk, Dorothy; Seethala, Ramakrishna; Sun, Huabin; Li, Danshi; Burford, Neil T.; Stoffel, Robert H.; Salyan, Mary Ellen (2004-03-25). "Discovery of a potent and novel motilin agonist". Journal of Medicinal Chemistry. 47 (7): 1704–1708. doi:10.1021/jm0304865. ISSN 0022-2623. PMID 15027861.
- ^ Schmidt, P. J.; Yokoyama, M.; McGinniss, M. H.; Levin, R. H. (November 1965). "Erythroid homograft following leukocyte transfusion in a patient with acute leukemia. II. Serologic and immunochemical studies". Blood. 26 (5): 597–609. doi:10.1182/blood.V26.5.597.597. ISSN 0006-4971. PMID 5321111.
- ^ Martinez-Sanz, Juan; Yang, Ao; Blouquit, Yves; Duchambon, Patricia; Assairi, Liliane; Craescu, Constantin T. (October 2006). "Binding of human centrin 2 to the centrosomal protein hSfi1". The FEBS Journal. 273 (19): 4504–4515. doi:10.1111/j.1742-4658.2006.05456.x. ISSN 1742-464X. PMID 16956364.
Further reading
[edit]- Hennig, Michael; D′Arcy, Allan; Hampele, Isabella C.; Page, Malcolm G. P.; Oefner, Christian; Dale, Glenn E. (May 1998). "Crystal structure and reaction mechanism of 7,8-dihydroneopterin aldolase from staphylococcus aureus". Nature Structural Biology. 5 (5): 357–362. doi:10.1038/nsb0598-357. ISSN 1545-9985.
- Sanders, William J.; Nienaber, Vicki L.; Lerner, Claude G.; McCall, J. Owen; Merrick, Sean M.; Swanson, Susan J.; Harlan, John E.; Stoll, Vincent S.; Stamper, Geoffrey F.; Betz, Stephen F.; Condroski, Kevin R.; Meadows, Robert P.; Severin, Jean M.; Walter, Karl A.; Magdalinos, Peter (2004-03-01). "Discovery of Potent Inhibitors of Dihydroneopterin Aldolase Using CrystaLEAD High-Throughput X-ray Crystallographic Screening and Structure-Directed Lead Optimization". Journal of Medicinal Chemistry. 47 (7): 1709–1718. doi:10.1021/jm030497y. ISSN 0022-2623. PMID 15027862.
- Wang, Yi; Li, Yue; Yan, Honggao (2006-12-01). "Mechanism of Dihydroneopterin Aldolase: Functional Roles of the Conserved Active Site Glutamate and Lysine Residues". Biochemistry. 45 (51): 15232–15239. doi:10.1021/bi060949j. ISSN 0006-2960. PMC 3018710. PMID 17176045.
- Czeczot, Alexia de Matos; Muniz, Mauro Neves; Perelló, Marcia Alberton; Silva, Éverton Edésio Dinis; Timmers, Luís Fernando Saraiva Macedo; Berger, Andresa; Gonzalez, Laura Calle; Arraché Gonçalves, Guilherme; Moura, Sidnei; Machado, Pablo; Bizarro, Cristiano Valim; Basso, Luiz Augusto (2024-12-31). "Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity". Journal of Enzyme Inhibition and Medicinal Chemistry. 39 (1). doi:10.1080/14756366.2024.2388207. ISSN 1475-6366.
- Garçon, Arnaud; Levy, Colin; Derrick, Jeremy P. (July 2006). "Crystal Structure of the Bifunctional Dihydroneopterin Aldolase/6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Streptococcus pneumoniae". Journal of Molecular Biology. 360 (3): 644–653. doi:10.1016/j.jmb.2006.05.038. PMID 16781731.
- Hitchings, George H.; Burchall, James J. (January 1965), Nord, F. F. (ed.), Inhibition of Folate Biosynthesis and Function as a Basis for Chemotherapy, Advances in Enzymology - and Related Areas of Molecular Biology, vol. 27 (1 ed.), Wiley, pp. 417–468, doi:10.1002/9780470122723.ch9, ISBN 978-0-470-12498-7, PMID 4387360, retrieved 2024-12-09
- Bermingham, Alun; Derrick, Jeremy P. (July 2002). "The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery". BioEssays. 24 (7): 637–648. doi:10.1002/bies.10114. ISSN 0265-9247. PMID 12111724.
- Mathis JB, Brown GM (1970). "The biosynthesis of folic acid. XI. Purification and properties of dihydroneopterin aldolase". J. Biol. Chem. 245 (11): 3015–25. doi:10.1016/S0021-9258(18)63090-X. PMID 4912541.
External links
[edit]
Media related to Dihydroneopterin aldolase at Wikimedia Commons
