Article
Chemistry, Organic
Jian Fu, Huixiao Fu, Yufen Xia, Ines N'Go, Jun Cao, Weidong Pan, Stephane P. Vincent
Summary: An in situ screening assay has been developed to discover novel inhibitors of UDP-galactopyranose mutase, a key enzyme in Mycobacterium tuberculosis cell wall biosynthesis. This technology allows for high-throughput synthesis and screening of enzyme inhibitors in a 384-well plate format, leading to the successful identification of UGM ligands and determination of their inhibition levels. This study provides a blueprint for designing enamide structures as new UGM inhibitors and anti-mycobacterial agents.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Dalia M. Ahmed, Jeffrey M. Chen, David A. R. Sanders
Summary: UDP-galactopyranose mutase (UGM) is an essential enzyme involved in bacterial cell wall synthesis. A compound called MS208, which acts as a mixed inhibitor of MtbUGM, has been identified as a potential drug target for developing antituberculosis agents. Further studies were conducted to analyze the structure-activity relationship of MS208 and its analogues, and it was found that while most compounds showed inhibitory activity against MtbUGM, they did not inhibit the growth of Mycobacterium tuberculosis.
Article
Biochemistry & Molecular Biology
Dalia M. Ahmed, David A. R. Sanders
Summary: In this study, an integrated biophysical approach was used to investigate the aggregation behavior of MS208 and its analogues against MtUGM, revealing unexpected aggregation behavior.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Jian Fu, Ziyao He, Huixiao Fu, Yufen Xia, Ines N'Go, Huayong Lou, Jinglan Wu, Weidong Pan, Stephane P. Vincent
Summary: The lack of effective TB treatments due to drug-resistant TB has led to limited drug development activity in this area. This study focuses on the inhibition of the UGM enzyme, which is involved in the biosynthesis of galactan. The synthesized amides derived from rosmarinic acid showed a higher affinity for UGM compared to the corresponding esters. In particular, compound 5h demonstrated interesting binding affinity values. A new UGM SPR assay was also established to confirm the binding of compound 5h to UGM. Overall, this study validates the use of amide bioisosteric strategy for the development of UGM inhibitors from rosmarinic acid.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Brian S. Mantilla, Cristina Azevedo, Paul W. Denny, Adolfo Saiardi, Roberto Docampo
Summary: This study reveals the crucial role of histidine ammonia lyase (HAL) in the alkalinization of acidocalcisomes by binding to polyphosphate and regulating its function through lysine residues in the C-terminal region. HAL localization and inhibition by polyP demonstrate a mechanism for acidocalcisome alkalinization linked to amino acid metabolism.
Article
Biochemistry & Molecular Biology
Xueqing Du, Xuan Chu, Ning Liu, Xiaoyu Jia, Hui Peng, Yazhong Xiao, Lin Liu, Haizhu Yu, Fudong Li, Chao He
Summary: Members of GT75 family catalyze autoglycosylation and exhibit NDP-pyranose mutase activity. Crystal structures of MtdL in complex with Mn2+ and GDP reveal key residues involved in substrate binding and catalytic reactions. Our results provide insights into the mechanism of NDP-pyranose mutase and highlight the importance of this enzyme family in furanose biosynthesis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Microbiology
Chihiro Kadooka, Yutaka Tanaka, Daisuke Hira, Jun-ichi Maruyama, Masatoshi Goto, Takuji Oka
Summary: This study confirms the presence of D-galactofuranose-containing glycans in Aspergillus oryzae and shows that they play an important role in cell wall integrity. Deletion of the ugmA gene affects mycelial elongation and the structure of the cell wall.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Hui Zhou, Yueqiang Xu, Frank Ebel, Cheng Jin
Summary: The study investigated the impact of ugmA, ugmB, and gfsB gene mutations in F. oxysporum f.sp. cucumerinum on its morphogenesis and pathogenicity. Results showed that deletion of the ugmA gene led to various phenotypic abnormalities, including reduced galactofuranose content, slowed growth, impaired conidiation, and loss of pathogenicity in cucumber plantlets.
Article
Biotechnology & Applied Microbiology
Shulin Cao, Wenqiang Jiang, Yan Shu, Wei Li, Yani Zhang, Aixiang Zhang, Huaigu Chen
Summary: In this study, the CHY1-interacting protein UGMA was identified and confirmed with yeast two-hybrid assays. Deletion of UGMA led to significant defects in growth, reproduction, cell wall integrity, and pathogenicity in F. graminearum. UGMA is unique to fungi and bacteria and plays an important role as a pathogenic factor, required for cell wall architecture, radial growth, and caspofungin tolerance, making it a promising target for antifungal agent development.
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
J. Santos, S. H. Fernandez Villamil, J. M. Delfino, W. M. Valsecchi
Summary: Computational studies are used to predict drug-target interactions as a means of identifying new druggable targets for neglected diseases. The enzyme HPRT is essential for the survival of the parasite T. cruzi, the causal agent of Chagas disease. Comparative structural analysis revealed functional differences between TcHPRT and HsHPRT, indicating potential therapeutic approaches based on their different quaternary arrangements and structural features.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Claudia Lopez-Lira, Ricardo A. Tapia, Alejandra Herrera, Michel Lapier, Juan D. Maya, Jorge Soto-Delgado, Allen G. Oliver, A. Graham Lappin, Eugenio Uriarte
Summary: The design and synthesis of new 2-phenyl(pyridinyl)benzimidazolequinones and their 5-phenoxy derivatives demonstrate potent anti-Trypanosoma cruzi activity. Compound 11a shows significantly higher activity compared to nifurtimox. Molecular docking studies suggest that these compounds could have a multitarget profile.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Florencia Mosquillo, Gonzalo Scalese, Rodrigo Moreira, Pablo A. Denis, Ignacio Machado, Margot Paulino, Dinorah Gambino, Leticia Perez-Diaz
Summary: The current treatment for Chagas' disease using Nifurtimox and Benznidazol has limitations, highlighting the need for new drugs. Two metal-based compounds, Pd-dppf-mpo and Pt-dppf-mpo, were characterized and found to have trypanocidal activity. Through omics studies and validation experiments, it was determined that these compounds inhibit the enzymes phosphomevalonate kinase and lanosterol 14-α-demethylase to exert their therapeutic effects.
Article
Biochemistry & Molecular Biology
Alessandro Bonardi, Seppo Parkkila, Claudiu T. Supuran
Summary: This study investigated the inhibition of the alpha-class carbonic anhydrase from Trypanosoma cruzi with phenols, which have a different mechanism of inhibition compared to previously studied compounds. The results showed that certain phenols were effective inhibitors of the enzyme, suggesting their potential as antiprotozoal agents.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Salvatore G. De-Simone, Saulo C. Bourguignon, Priscila S. Goncalves, Guilherme C. Lechuga, David W. Provance Jr
Summary: This study investigated the energetic metabolism of T. cruzi during metacyclogenesis and provided insights into its differential metabolic modifications. It improved the understanding of T. cruzi metabolism by measuring enzymatic activities and organic acid concentrations.
Article
Biochemistry & Molecular Biology
Sumit Das, Puja Panja, Gaurab Chowdhury, Saroj Biswas, Yuthika Dholey, Subrata Adak
Summary: This study reports two members of the ChaC family of gamma-glutamyl cyclotransferases in Leishmania, showing their roles in GSH degradation and cell growth.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
David A. Korasick, John J. Tanner
Summary: Certain mutations in the ALDH7A1 gene cause pyridoxine-dependent epilepsy (PDE), characterized by seizures and sometimes intellectual disability. These mutations, including over 70 missense mutations, have complex effects on the structure and catalytic activity of ALDH7A1. Mutations targeting active site residues and those remote from the site show varied impact, indicating the challenge in predicting the effects of missense mutations on enzyme function. Additional biophysical analyses of disease-causing mutations are necessary to develop predictive rules for enzyme structure and function.
Article
Biochemistry & Molecular Biology
Ashley C. Campbell, Austin R. Prater, Alexandra N. Bogner, Thomas P. Quinn, Kent S. Gates, Donald F. Becker, John J. Tanner
Summary: The discovery of a new class of PRODH inactivator that covalently and irreversibly modifies the FAD in a light-dependent manner provides a new approach for developing photopharmacological drugs targeting cancer cells. The inactivation process involves exposure to bright white light, leading to irreversible loss of enzyme activity and potential photosensitivity of cancer cells.
ACS CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Alexandra N. Bogner, Kyle M. Stiers, Cole M. McKay, Donald F. Becker, John J. Tanner
Summary: ALDH4A1 is a dual substrate enzyme involved in the final steps of proline and hydroxyproline catabolism. The study found that trans-4-hydroxy-L-proline is the strongest inhibitor of ALDH4A1, with a competitive inhibition constant of 0.7 mM.
Article
Virology
Ashley C. Campbell, John J. Tanner, Kurt L. Krause
Summary: This study presents a method for producing neuraminidase from a human cell line, which yielded high levels of soluble expression and supported high resolution crystal structure determination. The method is expected to be useful in further studies, such as the characterization of inhibitor binding.
Article
Chemistry, Multidisciplinary
Hannah Valentino, David A. Korasick, Tabbetha J. Bohac, Justin A. Shapiro, Timothy A. Wencewicz, John J. Tanner, Pablo Sobrado
Summary: Acinetobacter baumannii is an opportunistic pathogen with a high mortality rate, and the synthesis and uptake of iron-chelating siderophores Acinetobactin (Acb) and preacinetobactin (pre-Acb) are crucial for its virulence. The flavin-dependent siderophore-interacting protein (SIP) BauF plays a key role in the reduction of Fe(III) bound to Acb/pre-Acb and the release of Fe(II), with NAD(P)H not being its physiological partners. The structural and biochemical data presented validate the importance of BauF in A. baumannii iron assimilation, providing valuable information for drug design.
Article
Biochemistry & Molecular Biology
Sagar M. Patel, Javier Seravalli, Kyle M. Stiers, John J. Tanner, Donald F. Becker
Summary: L-Thioproline is a cyclic sulfur-containing analog of l-proline found in various organisms, and human PYCR isozymes 1 and 2 show significant dehydrogenase activity towards L-T4C. This suggests a new enzyme function for PYCRs in the metabolism of L-T4C, leading to cysteine formation.
Article
Biochemistry & Molecular Biology
David A. Korasick, Shelbi L. Christgen, Insaf A. Qureshi, Donald F. Becker, John J. Tanner
Summary: This study investigated the mechanism of proline utilization enzyme in bacteria using tunnel-blocking mutagenesis, revealing that Trp206 plays a crucial role in inhibiting the auxiliary tunnel 2a and impairing PRODH activity. Further experiments indicated that Trp206 may affect the binding of L-proline substrate and the closure of the PRODH active site by disrupting a specific ion pair.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Yizi Mao, Javier Seravalli, Thomas G. Smith, Martha Morton, John J. Tanner, Donald F. Becker
Summary: Thiazolidine carboxylates T4C and T2C, sulfur analogues of proline, are substrates for the enzyme PutA, which catalyzes their oxidation. The oxidation of T4C leads to cysteine formation, while oxidation of T2C generates a stable Delta(4)-thiazoline-2-carboxylate species.
Article
Chemistry, Organic
Alexandra N. Bogner, John J. Tanner
Summary: In this study, the inhibition of PRODH by 18 proline-like compounds was investigated to understand the structural and chemical features responsible for the affinity of the best-known inhibitor. The results revealed new structure-affinity relationships that could be utilized in the development of new inhibitor design strategies targeting PRODH.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Noah S. Lyons, John J. Tanner, Alexandra N. Bogner, Pablo Sobrado
Summary: Acinetobacter baumannii is a Gram-negative opportunistic pathogen that causes nosocomial infections. The rise of multidrug resistant strains of A. baumannii has limited the use of standard antibiotics, highlighting a need for new drugs that exploit novel mechanisms of pathogenicity. This study investigated FbsI, an N-hydroxylating monooxygenase involved in the biosynthesis of the major siderophore produced by A. baumannii. The results provide insights into the substrate recognition and catalytic cycle of FbsI, and have implications for understanding the pathogenic mechanisms and developing new antibiotics.
Article
Biochemistry & Molecular Biology
Kaylen R. Meeks, John J. Tanner
Summary: PYCRs are important enzymes involved in the biosynthesis of proline. They have been extensively studied in cancer, especially PYCR1, due to their role in altered metabolism. This study presents a method for expressing and purifying PYCR3 in E. coli. It shows that the activity of PYCR3 is dependent on the type of coenzyme used. Competitive inhibition assays were performed with proline analogs, and a higher selectivity for PYCR1 than PYCR3 was observed with N-formyl-L-proline.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Biochemistry & Molecular Biology
David A. Korasick, Luckio F. Owuocha, Pramod K. Kandoth, John J. Tanner, Melissa G. Mitchum, Lesa J. Beamer
Summary: This study investigates the effects of single variants P130R and N358Y in soybean SHMT8. The results demonstrate that these two variants have reduced catalytic activity compared to the susceptible Essex SHMT8, but are more active than the P130R/N368Y double variant. Additionally, the single variants lack THF-substrate inhibition, unlike Essex SHMT8. The crystal structures of the variants provide insights into the structural impacts of the mutations and allosteric regulation.
Article
Multidisciplinary Sciences
Cole E. E. McKay, Jianlin Cheng, John J. J. Tanner
Summary: The crystal structure of the domain of unknown function family 507 protein from Aquifex aeolicus was determined, revealing a Y-shaped α-helical structure with pseudo-twofold symmetry. The structures differ in their C-terminal arm rotation, suggesting a potential functional site.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
David P. Buckley, Marie E. Migaud, John J. Tanner
Summary: ox-NADs are redox inactive derivatives of NAD that accumulate in cells under stress and may act as potential inhibitors of enzymes. Molecular dynamics simulations reveal distinct conformational preferences of ox-NADs in solution, which could aid in identifying enzymes targeted by ox-NADs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Alexandra N. Bogner, Juan Ji, John J. Tanner
Summary: In this study, minimal PRODH domains have been engineered for inhibitor discovery, with designs containing approximately one-third of the PutA amino acid sequence and replacing a domain of PutA. The minimal PRODHs exhibit near wild-type enzymatic activity and are susceptible to known inhibitors and inactivators. Crystal structures of minimal PRODHs inhibited by specific compounds were determined, showing potential usefulness in chemical probe discovery.
PROTEIN ENGINEERING DESIGN & SELECTION
(2022)