l-Histidinol Dehydrogenase (HDH) Represents a Potential Molecular Target of Herbicides, Bactericides, and Fungicides

InfoMetricsFiguresRef.SI Journal of Agricultural and Food ChemistryASAPArticle This publication is free to access through this site. Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse ViewpointFebruary 18, 2025l-Histidinol Dehydrogenase (HDH) Represents a Potential Molecular Target of Herbicides, Bactericides, and FungicidesClick to copy article linkArticle link copied!Xing-Xing Shi*Xing-Xing ShiState Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. China*[email protected]More by Xing-Xing ShiHui-Min ChenHui-Min ChenState Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaMore by Hui-Min ChenWu-Yingzheng GuoWu-Yingzheng GuoState Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaMore by Wu-Yingzheng GuoZhi-Zheng WangZhi-Zheng WangState Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430061, P. R. ChinaMore by Zhi-Zheng Wanghttps://orcid.org/0009-0009-4847-5797Ying YeYing YeState Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaMore by Ying YeGuang-Fu Yang*Guang-Fu YangState Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. China*[email protected]More by Guang-Fu Yanghttps://orcid.org/0000-0003-4384-2593Open PDFJournal of Agricultural and Food ChemistryCite this: J. Agric. Food Chem. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acs.jafc.5c01206https://doi.org/10.1021/acs.jafc.5c01206Published February 18, 2025 Publication History Received 25 January 2025Published online 18 February 2025article-commentary© 2025 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS Publications© 2025 American Chemical SocietySubjectswhat are subjectsArticle subjects are automatically applied from the ACS Subject Taxonomy and describe the scientific concepts and themes of the article.BacteriaInhibitorsMonomersPeptides and proteinsPest controlThe global population is projected to reach nearly 10 billion by 2050, posing enormous challenges for worldwide agricultural production. The use of pesticides is one of the most cost-effective means to increase food productivity by protecting crops from weeds, diseases, and insect infestation. Twenty to forty percent of the world's total crop yield loss could be saved by pesticides each year.Nevertheless, with the overuse of traditional pesticides, many agricultural pests have developed resistance to them. Since the late 19th century, the number of cases of resistance to herbicides, fungicides, and insecticides has increased dramatically. Pesticide resistance can easily cause the failure of pesticides or other compounds with the same mode of action, costing agriculture billions of dollars each year. The problem of pesticide resistance poses a serious threat to sustainable food production. In this context, the development of pesticides based on novel targets has become one of the most effective strategies to address resistance and ensure food security.Function and Structure of HDHClick to copy section linkSection link copied!l-Histidinol dehydrogenase (HDH) is essential for primary metabolism in bacteria, fungi, lower eukaryotes, and plants by participating in histidine biosynthesis (Figure 1A). Among the 20 natural amino acid, histidine is the most versatile in protein structures or biological functions. For example, histidine is often the key residue in enzyme catalytic sites. HDH catalyzes the final two steps in the histidine biosynthesis pathway, oxidizing l-histidinol via l-histidinal into l-histidine. A loss of HDH function impairs histidine biosynthesis and often results in abnormal phenotypes. The knockout of hisn8, the HDH gene in Arabidopsis, showed ovule abortion phenotypes. (1) BsHDH has been identified as an essential factor for its intracellular replication in macrophages. (2) Inhibition of HDH activity can reduce the in vitro growth and intramacrophagic multiplication of Brucella suis. (3) Similarly, histidine auxotroph mutants of Mycobacterium tuberculosis, Salmonella typhimurium, or Burkholderia pseudomallei showed reduced virulence. (4) In addition to bacteria, deletion of the essential gene in the histidine biosynthesis pathway in the fungus Aspergillus fumigatus leads to attenuated pathogenicity and decreased resistance to starvation. (5) Notably, HDH is absent in humans and other mammals. Therefore, targeting HDH to block the histidine biosynthesis pathway provides a promising path for the development of novel herbicides, bactericides, and fungicides.Figure 1Figure 1. (A) HDH-catalyzed oxidation reaction and HDH-related biological functions. (B) Homodimeric structure of MtHDH. (C) Structure of MtHDH in a complex with histidine and NAD+ (Protein Data Bank entry 5VLD). (D) Evolutionary conservation of HDH. (E) Reported HDH inhibitors.High Resolution ImageDownload MS PowerPoint SlideHDH is a Zn2+- and NAD+-dependent enzyme with a dimeric nature (Figure 1B). Some HDH crystal structures have been reported, covering Escherichia coli, Elizabethkingia anopheles, B. suis, and Medicago truncatula. The overall architecture of these HDH structures is similar. Among plant species, only MtHDH has been structurally characterized and is described here as an example (Figure 1C). The MtHDH monomer consists of four domains (I–IV). Domains I and II adopt a Rossmann fold in their core and together constitute a globular architecture with a cleft at their interface. Domain III is almost perpendicular to domain IV, and they together form an L-shaped tail occupying the cleft between domains I and II in the other monomer. Surrounded by domains I, II, and IV, the active site is located at the dimer interface, containing a substrate-binding subpocket and a cofactor NAD+-binding groove. In the substrate-binding pocket, Zn2+ is octahedrally coordinated to residues Gln299, Asp401, His460*, and His302 and the two nitrogen atoms of l-histidinol. NAD+ binds to only one monomer primarily through polar interactions. In the catalytic mechanism of MtHDH, Zn2+ is critical for the proper positioning of the substrate and other reaction intermediates, while NAD+ binding allows for hydride transfer and requires specific loop rearrangement induced by substrate binding. (6) Although the degree of sequence similarity of HDH among different species is relatively low, the active site is highly conserved (Figure 1D). These structural and mechanistic studies of HDH provide a basis for designing novel inhibitors as pesticide leads.Progress in HDH Inhibitor DiscoveryClick to copy section linkSection link copied!In recent decades, a number of plant or bacterial HDH inhibitors have been reported (Figure 1E). (7,8) Most of the existing HDH inhibitors contain a (R)-(α)-methylhistamine fragment, which is also the party of the substrate histidinol that coordinates with Zn2+. In 1989, histidinol analogue compound 1 (Ki = 35 μM) was found to exhibit micromolar inhibitory activity against StHDH. In 1996, a series derivative of compound 1 was reported to exhibit an inhibitory effect on BoHDH, among which compounds 2a and 2b showed better bioactivities (IC50 = 40 nM). In 2007, histidine-derived substituted benzylic ketones were synthesized as BsHDH inhibitors. Compound 3 was the most effective (IC50 = 3 nM) and exhibited good in vitro anti-B. suis activity. The crystal structure of BsHDH in a complex with compound 3 was later determined. (9) Two nitrogen atoms in the imidazole moiety and -NH2 group form two coordinate bonds with Zn2+, while the aromatic side chain forms a hydrophobic interaction with the surrounding residues and is directed toward the groove responsible for NAD+ recognition. In 2008, a series of BsHDH inhibitors containing sulfonyl hydrazide were reported, represented by compound 4 (IC50 = 25 μM). In 2012, via extension of the aromatic tail, compound 5 was obtained as a novel BsHDH inhibitor (IC50 = 3 nM), which had a certain inhibitory effect on B. suis growth and replication. In 2014, oxo- and thioxo-imidazo[1,5-c]pyrimidines was designed by replacing the aminomethyl imidazole moiety, but these compounds failed to improve the inhibitory effect on BsHDH. Compounds 6a (IC50 = 18 μM) and 6b (IC50 = 5 μM) showed relatively high bioactivities. In 2016, l-histidine-derived hydrazones were synthesized as the first low-micromolar M. tuberculosis (Mtb) HDH inhibitors. They showed moderate in vitro anti-Mtb activity, represented by compound 7 (IC50 = 1.1 nM). These inhibitors demonstrate the great potential of HDH as a novel molecular target for controlling plant growth or plant diseases.Future ProspectsClick to copy section linkSection link copied!This study highlights the potential of metalloenzyme HDH as a biochemical target for the development of herbicides, bactericides, and fungicides. Our retrospective investigation of HDH biological functions, structures, and inhibitors supports the good prospects for HDH-inhibiting pesticides, which present a novel mode of action to overcome resistance. In the future, the design of HDH inhibitors is a prospective direction for pesticide discovery.Author InformationClick to copy section linkSection link copied!Corresponding AuthorsXing-Xing Shi - State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. China; Email: [email protected]Guang-Fu Yang - State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. China; https://orcid.org/0000-0003-4384-2593; Email: [email protected]AuthorsHui-Min Chen - State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaWu-Yingzheng Guo - State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaZhi-Zheng Wang - State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430061, P. R. China; https://orcid.org/0009-0009-4847-5797Ying Ye - State Key Laboratory of Green Pesticide, Central China Normal University, Wuhan 430079, P. R. ChinaAuthor ContributionsX.-X.S. and H.-M.C. contributed equally to this work.NotesThe authors declare no competing financial interest.AcknowledgmentsClick to copy section linkSection link copied!This work was supported by the National Key Research and Development Program of China (2021YFD1700103), the fellowship from the China National Postdoctoral Program for Innovative Talent (BX20240133), the National Natural Science Foundation of China (22207037), the Postdoctoral Fellowship Program of CPSF (GZB20230198), the China Postdoctoral Science Foundation (2024M760857), and the Postdoctor Project of Hubei Province (2024HBBHCXA004).ReferencesClick to copy section linkSection link copied! This article references 9 other publications. 1Muralla, R.; Sweeney, C.; Stepansky, A.; Leustek, T.; Meinke, D. Genetic dissection of histidine biosynthesis in Arabidopsis. Plant Physiol. 2007, 144 (2), 890– 903, DOI: 10.1104/pp.107.096511 Google ScholarThere is no corresponding record for this reference.2Köhler, S.; Foulongne, V.; Ouahrani-Bettache, S.; Bourg, G.; Teyssier, J.; Ramuz, M.; Liautard, J. The analysis of the intramacrophagic virulome of Brucella suis deciphers the environment encountered by the pathogen inside the macrophage host cell. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (24), 15711– 15716, DOI: 10.1073/pnas.232454299 Google ScholarThere is no corresponding record for this reference.3Joseph, P.; Abdo, M. R.; Boigegrain, R. A.; Montero, J. L.; Winum, J. Y.; Kohler, S. Targeting of the Brucella suis virulence factor histidinol dehydrogenase by histidinol analogues results in inhibition of intramacrophagic multiplication of the pathogen. Antimicrob. Agents Chemother. 2007, 51 (10), 3752– 5, DOI: 10.1128/AAC.00572-07 Google ScholarThere is no corresponding record for this reference.4M. Monti, S.; De Simone, G.; D'Ambrosio, K. L-Histidinol Dehydrogenase as a New Target for Old Diseases. Curr. Top. Med. Chem. 2016, 16 (21), 2369– 2378, DOI: 10.2174/1568026616666160413140000 Google ScholarThere is no corresponding record for this reference.5Dietl, A. M.; Amich, J.; Leal, S.; Beckmann, N.; Binder, U.; Beilhack, A.; Pearlman, E.; Haas, H. Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus. Virulence 2016, 7 (4), 465– 76, DOI: 10.1080/21505594.2016.1146848 Google ScholarThere is no corresponding record for this reference.6Ruszkowski, M.; Dauter, Z. Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride. Sci. Rep. 2017, 7 (1), 10476, DOI: 10.1038/s41598-017-10859-0 Google ScholarThere is no corresponding record for this reference.7Lopez, M.; Köhler, S.; Winum, J.-Y. Zinc metalloenzymes as new targets against the bacterial pathogen Brucella. J. Inorg. Biochem. 2012, 111, 138– 145, DOI: 10.1016/j.jinorgbio.2011.10.019 Google ScholarThere is no corresponding record for this reference.8Winum, J.-Y. Chapter 3.7 - Histidinol dehydrogenase. In Metalloenzymes; Supuran, C. T., Donald, W. A., Eds.; Academic Press, 2024; pp 255– 263.Google ScholarThere is no corresponding record for this reference.9D'Ambrosio, K.; Lopez, M.; Dathan, N. A.; Ouahrani-Bettache, S.; Köhler, S.; Ascione, G.; Monti, S. M.; Winum, J.-Y.; De Simone, G. Structural basis for the rational design of new anti-Brucella agents: The crystal structure of the C366S mutant of l-histidinol dehydrogenase from Brucella suis. Biochimie 2014, 97, 114– 120, DOI: 10.1016/j.biochi.2013.09.028 Google ScholarThere is no corresponding record for this reference.Cited By Click to copy section linkSection link copied!This article has not yet been cited by other publications.Download PDFFiguresReferencesSupporting Information Get e-AlertsGet e-AlertsJournal of Agricultural and Food ChemistryCite this: J. Agric. Food Chem. 2025, XXXX, XXX, XXX-XXXClick to copy citationCitation copied!https://doi.org/10.1021/acs.jafc.5c01206Published February 18, 2025 Publication History Received 25 January 2025Published online 18 February 2025© 2025 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsArticle Views-Altmetric-Citations-Learn about these metrics closeArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Recommended Articles FiguresReferencesSupporting InfoAbstractHigh Resolution ImageDownload MS PowerPoint SlideFigure 1Figure 1. (A) HDH-catalyzed oxidation reaction and HDH-related biological functions. (B) Homodimeric structure of MtHDH. (C) Structure of MtHDH in a complex with histidine and NAD+ (Protein Data Bank entry 5VLD). (D) Evolutionary conservation of HDH. (E) Reported HDH inhibitors.High Resolution ImageDownload MS PowerPoint SlideReferences This article references 9 other publications. 1Muralla, R.; Sweeney, C.; Stepansky, A.; Leustek, T.; Meinke, D. Genetic dissection of histidine biosynthesis in Arabidopsis. Plant Physiol. 2007, 144 (2), 890– 903, DOI: 10.1104/pp.107.096511 There is no corresponding record for this reference.2Köhler, S.; Foulongne, V.; Ouahrani-Bettache, S.; Bourg, G.; Teyssier, J.; Ramuz, M.; Liautard, J. The analysis of the intramacrophagic virulome of Brucella suis deciphers the environment encountered by the pathogen inside the macrophage host cell. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (24), 15711– 15716, DOI: 10.1073/pnas.232454299 There is no corresponding record for this reference.3Joseph, P.; Abdo, M. R.; Boigegrain, R. A.; Montero, J. L.; Winum, J. Y.; Kohler, S. Targeting of the Brucella suis virulence factor histidinol dehydrogenase by histidinol analogues results in inhibition of intramacrophagic multiplication of the pathogen. Antimicrob. Agents Chemother. 2007, 51 (10), 3752– 5, DOI: 10.1128/AAC.00572-07 There is no corresponding record for this reference.4M. Monti, S.; De Simone, G.; D'Ambrosio, K. L-Histidinol Dehydrogenase as a New Target for Old Diseases. Curr. Top. Med. Chem. 2016, 16 (21), 2369– 2378, DOI: 10.2174/1568026616666160413140000 There is no corresponding record for this reference.5Dietl, A. M.; Amich, J.; Leal, S.; Beckmann, N.; Binder, U.; Beilhack, A.; Pearlman, E.; Haas, H. Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus. Virulence 2016, 7 (4), 465– 76, DOI: 10.1080/21505594.2016.1146848 There is no corresponding record for this reference.6Ruszkowski, M.; Dauter, Z. Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride. Sci. Rep. 2017, 7 (1), 10476, DOI: 10.1038/s41598-017-10859-0 There is no corresponding record for this reference.7Lopez, M.; Köhler, S.; Winum, J.-Y. Zinc metalloenzymes as new targets against the bacterial pathogen Brucella. J. Inorg. Biochem. 2012, 111, 138– 145, DOI: 10.1016/j.jinorgbio.2011.10.019 There is no corresponding record for this reference.8Winum, J.-Y. Chapter 3.7 - Histidinol dehydrogenase. In Metalloenzymes; Supuran, C. T., Donald, W. A., Eds.; Academic Press, 2024; pp 255– 263.There is no corresponding record for this reference.9D'Ambrosio, K.; Lopez, M.; Dathan, N. A.; Ouahrani-Bettache, S.; Köhler, S.; Ascione, G.; Monti, S. M.; Winum, J.-Y.; De Simone, G. Structural basis for the rational design of new anti-Brucella agents: The crystal structure of the C366S mutant of l-histidinol dehydrogenase from Brucella suis. Biochimie 2014, 97, 114– 120, DOI: 10.1016/j.biochi.2013.09.028 There is no corresponding record for this reference.PDB: 5VLD