PoMZ_10221 in *Pyricularia oryzae*: Dihydroorotate Dehydrogenase (DHODH) and its Role OpenAI o3-deep-research-2025-06-26 61 citations 2025-11-08T15:26:20.385181

PoMZ_10221 in Pyricularia oryzae: Dihydroorotate Dehydrogenase (DHODH) and its Role

Identification and Core Function

Gene PoMZ_10221 of Pyricularia oryzae (Magnaporthe oryzae) encodes a dihydroorotate dehydrogenase (DHODH), an enzyme catalyzing the only redox step in de novo pyrimidine biosynthesis (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). Specifically, this flavin-dependent enzyme oxidizes dihydroorotate to orotate, producing the precursor needed for UMP (uridine monophosphate) synthesis (pmc.ncbi.nlm.nih.gov). The reaction uses a flavin mononucleotide (FMN) cofactor and is coupled to reduction of a quinone electron acceptor (pmc.ncbi.nlm.nih.gov). In P. oryzae, as in other eukaryotes, DHODH is a class II enzyme that transfers electrons to ubiquinone in the mitochondrial respiratory chain (pubmed.ncbi.nlm.nih.gov). This reaction is highly substrate-specific – dihydroorotate is the specific substrate, and orotate the product – forming a crucial link in pyrimidine nucleotide biosynthesis (pmc.ncbi.nlm.nih.gov). Because it supplies orotate for UMP production, DHODH activity is essential for nucleotide synthesis and cellular replication (pmc.ncbi.nlm.nih.gov). It is the fourth step of the pathway and the sole oxidation step, making it a key metabolic choke-point (pubmed.ncbi.nlm.nih.gov).

Cellular Localization and Mechanism

The PoMZ_10221 gene product operates inside mitochondria, anchored to the inner mitochondrial membrane. Class II DHODH enzymes possess an N-terminal domain that tethers them to the membrane and positions the FMN cofactor near the quinone pool (pubmed.ncbi.nlm.nih.gov). P. oryzae DHODH likely follows this paradigm: the enzyme’s N-terminus associates with the inner membrane, enabling it to use ubiquinone (coenzyme Q) as a second substrate in the oxidation of dihydroorotate (pubmed.ncbi.nlm.nih.gov). This membrane-associated topology is critical – electrons removed from dihydroorotate are passed through the FMN prosthetic group to ubiquinone, linking pyrimidine biosynthesis to the electron transport chain (pubmed.ncbi.nlm.nih.gov). In practical terms, PoMZ_10221’s enzyme creates orotate in the mitochondrial matrix, and concurrently reduces ubiquinone to ubiquinol in the membrane. The enzyme’s activity thus depends on the mitochondrial redox state, and it harnesses respiration to drive pyrimidine synthesis (pubmed.ncbi.nlm.nih.gov). Such integration in the mitochondrial inner membrane distinguishes class II DHODHs (found in fungi and mammals) from cytosolic class I enzymes in bacteria (pubmed.ncbi.nlm.nih.gov). The conserved residues in the active site and quinone-binding site of class II DHODH facilitate this electron transfer mechanism (pubmed.ncbi.nlm.nih.gov). In summary, PoMZ_10221’s product is a mitochondrial flavoprotein that couples dihydroorotate oxidation to the respiratory quinone cycle, reflecting its dual role in metabolism and energy coupling.

Biological Role and Pathways

As the catalyst of orotate production, PoMZ_10221’s enzyme is indispensable for the de novo pyrimidine biosynthetic pathway. This pathway supplies the UMP nucleotides required for RNA, DNA, and other vital molecules. Consequently, the loss of DHODH function is lethal unless exogenous pyrimidine (or orotate) is provided (pmc.ncbi.nlm.nih.gov). In P. oryzae, disruption of the PoMZ_10221 gene (often referred to as pyr4 in analogy to pyrimidine pathway genes) results in an auxotrophic mutant that cannot grow on minimal media, consistent with a block in pyrimidine biosynthesis (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This growth defect can be rescued by supplementing orotate (the product of the DHODH reaction), but not by adding dihydroorotate, confirming that the metabolic bottleneck is specifically at the DHODH step (pmc.ncbi.nlm.nih.gov). Under normal conditions, the enzyme’s activity is essential for P. oryzae to proliferate; without it, the fungus cannot synthesize UMP de novo and thus fails to produce RNA/DNA building blocks.

Importantly, PoMZ_10221’s role extends to the fungus’s pathogenicity. P. oryzae mutants lacking a functional DHODH are non-pathogenic on rice – they cannot cause disease symptoms in host plants (pmc.ncbi.nlm.nih.gov). In experimental studies, a P. oryzae strain with the PoMZ_10221/DHODH gene knocked out was unable to induce rice blast lesions (pmc.ncbi.nlm.nih.gov). This avirulence is explained by the mutant’s inability to sustain growth in planta: plant tissues do not supply the pathogen with orotate or uracil, so a DHODH-deficient fungus is starved for pyrimidines and fails to propagate. Thus, beyond basic cell viability, PoMZ_10221 is critical for virulence, making pyrimidine biosynthesis a dependency for infection. This finding underscores a broader point: fundamental metabolic pathways (like nucleotide biosynthesis) can be essential for pathogenic growth in the host context (pmc.ncbi.nlm.nih.gov). In summary, PoMZ_10221 participates in the core pyrimidine generation pathway, and its activity is a prerequisite for both normal fungal growth and disease-causing ability.

Recent Research and Applications in Disease Control

Because of its essential function, the PoMZ_10221-encoded DHODH has become a focus of recent antifungal research. Novel fungicides targeting this enzyme have been developed to exploit the pathogen’s dependence on de novo pyrimidine synthesis. One prominent example is quinofumelin, a fungicide introduced in 2022–2023 that specifically inhibits P. oryzae class II DHODH (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Quinofumelin’s mode of action was confirmed by biochemical and genetic evidence: the compound’s growth inhibition effect on P. oryzae is fully reversed by adding orotate (bypassing the blocked enzyme), but not by adding dihydroorotate (pmc.ncbi.nlm.nih.gov). This mirrors the phenotype of a pyr4 (DHODH) knockout mutant and pinpointed DHODH as the target site of quinofumelin (pmc.ncbi.nlm.nih.gov). In vitro, quinofumelin is a potent inhibitor of the P. oryzae DHODH enzyme, with a half-maximal inhibitory concentration (IC₅₀) of only ~2.8 nM (pmc.ncbi.nlm.nih.gov). Treated mycelia essentially cease growing unless the pathway end-product (orotate) is supplied (pmc.ncbi.nlm.nih.gov). Furthermore, P. oryzae strains in which the PoMZ_10221 gene was disrupted (ΔPopyr4 mutants) are markedly more sensitive to quinofumelin’s effects, and conversely, introducing a functional copy of the DHODH gene restores normal growth in the presence of the fungicide (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consistent with the enzyme’s vital role in infection, quinofumelin-treated fungi and pyr4-deletion mutants both failed to cause rice blast disease in experimental assays (pmc.ncbi.nlm.nih.gov). This validates DHODH as an anti-fungal target whose inhibition can protect plants by halting the pathogen’s proliferation.

A key advantage of targeting PoMZ_10221’s product is the selectivity achievable between fungal and host (plant or animal) enzymes. Recent studies have shown that quinofumelin is highly species-selective, inhibiting P. oryzae DHODH far more strongly than the human homolog (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In a 2023 analysis, Higashimura et al. reported that quinofumelin has about a 100,000-fold greater potency against P. oryzae DHODH than against human DHODH (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Structural comparisons indicate that differences in the ubiquinone-binding site of the fungal enzyme underlie this selectivity (pmc.ncbi.nlm.nih.gov). Notably, certain amino acid substitutions in the fungal DHODH (versus the human enzyme) allow quinofumelin to bind tightly to the fungal enzyme while barely affecting the human enzyme (pmc.ncbi.nlm.nih.gov). This means quinofumelin can shut down pyrimidine synthesis in the pathogen without harming the host’s cells – a desirable trait in fungicide design (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The strong fungal specificity also translates to a favorable toxicity profile: researchers emphasize that quinofumelin’s novel mode of action and high target selectivity suggest a low risk of off-target effects in crops or animals (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Given these properties, PoMZ_10221’s enzyme has emerged as an attractive fungicidal target. Experts note that a fungicide like quinofumelin, which hits a novel target (DHODH) and spares human enzymes, offers a valuable tool for managing blast disease and mitigating resistance to existing fungicides (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, current research and development efforts leverage the indispensability and diverged structure of P. oryzae DHODH – encoded by PoMZ_10221 – to achieve effective and selective disease control.

Summary of Key Points

Overall, gene PoMZ_10221’s product is a pivotal metabolic enzyme that operates in mitochondria to support nucleotide biosynthesis. Its activity is indispensable for the growth and pathogenicity of the rice blast fungus, and it is currently the focus of cutting-edge control strategies exploiting its unique enzymatic vulnerabilities (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

References: Recent primary literature and reviews have characterized the function and importance of P. oryzae DHODH. Higashimura et al. (2022) identified it as quinofumelin’s target and demonstrated orotate-rescuable growth inhibition (pmc.ncbi.nlm.nih.gov). In 2023, the same group quantified the enzyme’s fungal-vs-human selectivity (2.8 nM IC₅₀ for P. oryzae DHODH) and highlighted structural bases for specificity (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Additionally, Lin et al. (2023) showed via gene knockout that the DHODH (MoPyr4) is required for the fungus’s development and autophagy, reinforcing its central role in cell physiology (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Together, these studies paint a detailed picture of PoMZ_10221 as a critical enzyme in pyrimidine metabolism and a viable molecular target for controlling rice blast disease.

Citations

  1. AnnotationURLCitation(end_index=484, start_index=324, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  2. AnnotationURLCitation(end_index=638, start_index=485, title='Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron-sulphur cluster - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/11188687/#:~:text=Background%3A%20The%20fourth%20step%20and,use%20NAD%2B%20as%20the%20second')
  3. AnnotationURLCitation(end_index=956, start_index=796, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  4. AnnotationURLCitation(end_index=1234, start_index=1074, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  5. AnnotationURLCitation(end_index=1533, start_index=1385, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  6. AnnotationURLCitation(end_index=1873, start_index=1713, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  7. AnnotationURLCitation(end_index=2165, start_index=2005, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  8. AnnotationURLCitation(end_index=2424, start_index=2271, title='Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron-sulphur cluster - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/11188687/#:~:text=Background%3A%20The%20fourth%20step%20and,use%20NAD%2B%20as%20the%20second')
  9. AnnotationURLCitation(end_index=2848, start_index=2719, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,a%20key%20role%20in%20the')
  10. AnnotationURLCitation(end_index=3210, start_index=3062, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  11. AnnotationURLCitation(end_index=3573, start_index=3425, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  12. AnnotationURLCitation(end_index=3987, start_index=3858, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,a%20key%20role%20in%20the')
  13. AnnotationURLCitation(end_index=4273, start_index=4144, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,a%20key%20role%20in%20the')
  14. AnnotationURLCitation(end_index=4552, start_index=4404, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  15. AnnotationURLCitation(end_index=5265, start_index=5119, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  16. AnnotationURLCitation(end_index=5651, start_index=5505, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  17. AnnotationURLCitation(end_index=5792, start_index=5652, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  18. AnnotationURLCitation(end_index=6145, start_index=5999, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  19. AnnotationURLCitation(end_index=6689, start_index=6549, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  20. AnnotationURLCitation(end_index=6960, start_index=6820, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  21. AnnotationURLCitation(end_index=7629, start_index=7489, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  22. AnnotationURLCitation(end_index=8410, start_index=8250, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  23. AnnotationURLCitation(end_index=8535, start_index=8411, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=DHODH%20is%20present%20in%20many,HsDHODH')
  24. AnnotationURLCitation(end_index=8920, start_index=8774, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  25. AnnotationURLCitation(end_index=9205, start_index=9045, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  26. AnnotationURLCitation(end_index=9515, start_index=9357, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L163%20enzymes%20to,the%20enzymatic%20activity%20of%20%CE%94N')
  27. AnnotationURLCitation(end_index=9758, start_index=9612, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  28. AnnotationURLCitation(end_index=10179, start_index=10031, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L174%20Next%2C%20to,CZA%20plate%29%20was%20examined')
  29. AnnotationURLCitation(end_index=10352, start_index=10180, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  30. AnnotationURLCitation(end_index=10666, start_index=10526, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  31. AnnotationURLCitation(end_index=11202, start_index=11078, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=DHODH%20is%20present%20in%20many,HsDHODH')
  32. AnnotationURLCitation(end_index=11361, start_index=11203, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L170%20about%2010%5E%7B5%7D,over%20that%20of%20fungal%20DHODH')
  33. AnnotationURLCitation(end_index=11683, start_index=11525, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L170%20about%2010%5E%7B5%7D,over%20that%20of%20fungal%20DHODH')
  34. AnnotationURLCitation(end_index=11841, start_index=11684, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L246%20In%20this,in%20ubiquinone%20binding%20sites%20between')
  35. AnnotationURLCitation(end_index=12146, start_index=11974, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  36. AnnotationURLCitation(end_index=12504, start_index=12332, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  37. AnnotationURLCitation(end_index=12778, start_index=12654, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=DHODH%20is%20present%20in%20many,HsDHODH')
  38. AnnotationURLCitation(end_index=12936, start_index=12779, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L246%20In%20this,in%20ubiquinone%20binding%20sites%20between')
  39. AnnotationURLCitation(end_index=13301, start_index=13173, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=give%20quinofumelin%20a%20fungal%20DHODH,The')
  40. AnnotationURLCitation(end_index=13474, start_index=13302, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  41. AnnotationURLCitation(end_index=13952, start_index=13780, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  42. AnnotationURLCitation(end_index=14113, start_index=13953, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L250%20fungal%20and,options%20for%20managing%20plant%20diseases')
  43. AnnotationURLCitation(end_index=14717, start_index=14557, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  44. AnnotationURLCitation(end_index=14871, start_index=14718, title='Structure of dihydroorotate dehydrogenase B: electron transfer between two flavin groups bridged by an iron-sulphur cluster - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/11188687/#:~:text=Background%3A%20The%20fourth%20step%20and,use%20NAD%2B%20as%20the%20second')
  45. AnnotationURLCitation(end_index=15192, start_index=15044, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  46. AnnotationURLCitation(end_index=15646, start_index=15498, title='Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/15044733/#:~:text=comprising%20two%20alpha,The%20differences%20between%20the%20membrane')
  47. AnnotationURLCitation(end_index=16001, start_index=15855, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  48. AnnotationURLCitation(end_index=16247, start_index=16107, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  49. AnnotationURLCitation(end_index=16849, start_index=16689, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=inhibition%20was%20reversed%20by%20orotate,were%20not%20observed%20in%20rice')
  50. AnnotationURLCitation(end_index=17008, start_index=16850, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L163%20enzymes%20to,the%20enzymatic%20activity%20of%20%CE%94N')
  51. AnnotationURLCitation(end_index=17308, start_index=17150, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L170%20about%2010%5E%7B5%7D,over%20that%20of%20fungal%20DHODH')
  52. AnnotationURLCitation(end_index=17481, start_index=17309, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  53. AnnotationURLCitation(end_index=17810, start_index=17638, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  54. AnnotationURLCitation(end_index=17971, start_index=17811, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L250%20fungal%20and,options%20for%20managing%20plant%20diseases')
  55. AnnotationURLCitation(end_index=18453, start_index=18313, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=to%20antifungal%20activity,be%20the%20target%20site%20of')
  56. AnnotationURLCitation(end_index=18626, start_index=18454, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  57. AnnotationURLCitation(end_index=19018, start_index=18872, title='The target site of the novel fungicide quinofumelin, Pyricularia oryzae class II dihydroorotate dehydrogenase - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9716045/#:~:text=The%20target%20site%20of%20the,PoPYR4%29%20disruption%20mutant')
  58. AnnotationURLCitation(end_index=19339, start_index=19181, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=match%20at%20L163%20enzymes%20to,the%20enzymatic%20activity%20of%20%CE%94N')
  59. AnnotationURLCitation(end_index=19512, start_index=19340, title='Novel fungicide quinofumelin shows selectivity for fungal dihydroorotate dehydrogenase over the corresponding human enzyme - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9978249/#:~:text=In%20this%20study%2C%20quinofumelin%20showed,in%20ubiquinone%20binding%20sites%20between')
  60. AnnotationURLCitation(end_index=19846, start_index=19701, title='Dihydroorotase MoPyr4 is required for development, pathogenicity, and autophagy in rice blast fungus - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11247805/#:~:text=found%20that%20the%20protein%20in,to%20the%20name%20of%20the')
  61. AnnotationURLCitation(end_index=20007, start_index=19847, title='Dihydroorotase MoPyr4 is required for development, pathogenicity, and autophagy in rice blast fungus - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11247805/#:~:text=MoPyr4%2C%20encoded%20by%20the%20gene,core%20protein%20of%20the%20autophagy')