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HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II: A singular structure for a unique function

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PROTEIN SCIENCE 2024年第4期33卷 e4964-e4964页

作者： Bories, Pascaline Rima, Julie Tranier, Samuel Marcoux, Julien Grimoire, Yasmina Tomaszczyk, Mathilde Launay, Anne Fata, Karine Marrakchi, Hedia Burlet-Schiltz, Odile Mourey, Lionel Ducoux-Petit, Manuelle Bardou, Fabienne Bon, Cecile Quemard, Annaik Univ Toulouse III Paul Sabatier UPS Univ Toulouse Inst Pharmacol & Biol Structurale IPBS CNRS Toulouse France Univ Toulouse Univ Toulouse III Paul Sabatier UPS Serv TP Biochim Toulouse France IPBS CNRS UPS UMR5089 205 Route NarbonneBP 64182 F-31077 Toulouse 4 France

Worldwide, tuberculosis is the second leading infectious killer and multidrug resistance severely hampers disease control. Mycolic acids are a unique category of lipids that are essential for viability, virulence, and persistence of the causative agent, Mycobacterium tuberculosis (Mtb). Therefore, enzymes involved in mycolic acid biosynthesis represent an important class of drug targets. We previously showed that the (3R)-hydroxyacyl-ACP dehydratase (HAD) protein HadD is dedicated mainly to the production of ketomycolic acids and plays a determinant role in Mtb biofilm formation and virulence. Here, we discovered that HAD activity requires the formation of a tight heterotetramer between HadD and HadB, a HAD unit encoded by a distinct chromosomal region. Using biochemical, structural, and cell-based analyses, we showed that HadB is the catalytic subunit, whereas HadD is involved in substrate binding. Based on HadBDMtb crystal structure and substrate-bound models, we identified determinants of the ultra-long-chain lipid substrate specificity and revealed details of structure-function relationship. HadBDMtb unique function is partly due to a wider opening and a higher flexibility of the substrate-binding crevice in HadD, as well as the drastically truncated central alpha-helix of HadD hotdog fold, a feature described for the first time in a HAD enzyme. Taken together, our study shows that HadBDMtb, and not HadD alone, is the biologically relevant functional unit. These results have important implications for designing innovative antivirulence molecules to fight tuberculosis, as they suggest that the target to consider is not an isolated subunit, but the whole HadBD complex.

关键词： (3R)-hydroxyacyl-ACP dehydratase HadBD catalytic subunit crystal structure fatty acid synthase type II system hotdog helix Mycobacterium tuberculosis mycolic acids structure-function relationships substrate-binding subunit ultra-long-chain substrates

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Large-scale data-driven and physics-based models offer insights into the relationships among the structures,dynamics,and functions of chromosomes

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Journal of Molecular Cell Biology 2023年第6期15卷 11-24页

作者： Cibo Feng Jin Wang Xiakun Chu Advanced Materials Thrust Function HubThe Hong Kong University of Science and Technology(Guangzhou)Guangzhou 511400China Green e Materials Laboratory The Hong Kong University of Science and Technology(Guangzhou)Guangzhou 511400China College of Physics Jilin UniversityChangchun 130012China Department of Chemistry and Physics The State University of New York at Stony BrookStony BrookNY 11794USA Division of Life Science The Hong Kong University of Science and TechnologyHong Kong SAR 999077China Guangzhou Municipal Key Laboratory of Materials Informatics The Hong Kong University of Science and Technology(Guangzhou)Guangzhou 511400China

The organized three-dimensional chromosome architecture in the cell nucleus provides scaffolding for precise regulation of gene *** the cell changes its identity in the cell-fate decision-making process,extensive rearrangements of chromo-some structures occur accompanied by large-scale adaptations of gene expression,underscoring the importance of chromosome dynamics in shaping genome *** the last two decades,rapid development of experimental methods has provided unprecedented data to characterize the hierarchical structures and dynamic properties of *** parallel,these enormous data offer valuable opportunities for developing quantitative computational ***,we review a variety of large-scale polymer models developed to investigate the structures and dynamics of *** from the underlying modeling strategies,these approaches can be classified into data-driven(‘top-down’)and physics-based(‘bottom-up’)*** discuss their contributions to offering valuable insights into the relationships among the structures,dynamics,and functions of chromosomes and propose the perspective of developing data integration approaches from different experimental technologies and multidisciplinary theoretical/simulation methods combined with different modeling strategies.

关键词： 4D genome data-driven model physics-based model structure-function relationships cell-fate decision struc-tural changes chromosome dynamics

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Protein biochemistry and engineering drive the development of a carbonic anhydrase-based carbon dioxide sequestration strategy

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FEBS JOURNAL 2025年第10期292卷 2511-2514页

作者： Pollegioni, Loredano Molla, Gianluca Univ Insubria Dipartimento Biotecnol & Sci Vita Prot Factory 2 0 Via JH Dunant 3 I-21100 Varese Italy

The sequestration of carbon dioxide using carbonic anhydrase (CA) is one of the most effective methods for mitigating global warming. The burning of fossil fuels releases large quantities of flue gas;because of its high temperature and of the alkaline conditions required for CaCO3 precipitation in the mineralization process, thermo-alkali-stable CAs are needed. In this context, Manyumwa et al. conducted a biochemical characterization of three CAs derived from thermophilic bacteria. They then employed a rational design approach to enhance the specific activity and stability of the enzyme from the hydrothermal vent species Persephonella sp. KM09-Lau-8.

关键词： protein engineering reaction mechanism stabilization structure-function relationships

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HRCT quantitative analysis of airway remodeling and airway trapping in the small airway asthma phenotype and its correlation with pulmonary function

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JOURNAL OF ASTHMA 2023年第1期60卷 32-42页

作者： Lu, Dongzhu Yu, Qing Chen, Lichang Liao, Qiannuan Lan, Junkang Chen, Shu-Bing Wang, Cuilan Zeng, Wenyi Wu, Lingling Fan, Chaofan Lu, Peifeng Yu, Huapeng Southern Med Univ Zhujiang Hosp Dept Pulm & Crit Med 253 Ind Ave Guangzhou 510280 Guangdong Peoples R China Southern Med Univ Zhujiang Hosp Dept Radiol Guangzhou Peoples R China Southern Med Univ Shenzhen Hosp Dept Pulm & Crit Med Shenzhen Peoples R China

Objectives We aimed to explore whether large airway remodeling and small airway structural changes exist in subjects with small airway asthma phenotype and to evaluate the relationships between quantitative high-resolution computed tomography (qHRCT) parameters and lung function. Methods We enrolled 15 subjects with small airway asthma phenotype and 18 healthy controls. The two groups were matched by age, sex and body square area (BSA) with propensity score matching (PSM). Pulmonary function and qHRCT parameters [wall thickness (WT), wall area (WA), lumen area (LA), wall area percentage (WA%) of the 4th-6th generations in the right upper lobe apical segmental bronchus (RB1), adjusted by BSA, WT/BSA, WA/BSA, and LA/BSA, relative volume change -860 HU to -950 HU (RVC-860 to -950) and the expiration to inspiration ratio of mean lung density (MLDE/I)) were compared between the groups. Correlation analysis was employed to assess the relationship between qHRCT parameters and pulmonary function. Results The small airway asthma phenotype had significantly higher WA%, RVC-860 to -950 and MLDE/I and lower LA/BSA than the healthy control. Additionally, we found moderate to strong correlations between impulse oscillation (IOS) indices and WA6% and WT6/BSA. No significant correlation was found between bronchial parameters and air trapping parameters (p > 0.05). Conclusions Combining physiological tests with imaging approaches can lead to better evaluation of small airway disfunction (SAD) in asthmatic patients. Additionally, despite nonexistent airflow obstruction in patients with small airway asthma phenotype, large airway remodeling and small airway structural changes may appear simultaneously in the early stage of disease.

关键词： Nonexistent airflow obstruction airway structural changes structure-function relationships early stage propensity score matching

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Recent Advances in Mn,Fe,Co,and Ni-Catalyzed Organic Reactions

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CCS Chemistry 2024年第3期6卷 537-584页

作者： Lu-Jie Li Yuli He Yunhui Yang Jun Guo Zhan Lu Congyang Wang Shaolin Zhu Shou-Fei Zhu College of Chemistry Nankai UniversityTianjin 300071 School of Chemistry and Chemical Engineering Nanjing UniversityNanjingJiangsu Province 210093 Institute of Chemistry Chinese Academy of Sciences and University of Chinese Academy of SciencesBeijing 100190 Department of Chemistry Zhejiang UniversityHangzhouZhejiang Province 310058

This paper reviewed the recent research progress of organic reactions catalyzed by four typical earthabundant and 3d metal catalysts:Mn,Fe,Co,and Ni complexes and mainly focused on the reactions in which these 3d metal catalysts exhibited obvious advantages over other *** mechanism that makes these 3d metal catalysts show unusual properties is another focus of this *** outlook on 3d metal complexes-catalyzed organic reactions was also considered.

关键词： Earth-abundant metal catalysts sustainable organic synthesis structure-function relationships organometallic intermediates hydrocarbon transformations

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Characterizing functional modules in the human thalamus: coactivation-based parcellation and systems-level functional decoding

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BRAIN structure & function 2023年第8期228卷 1811-1834页

作者： Boeken, Ole J. J. Cieslik, Edna C. C. Langner, Robert Markett, Sebastian Humboldt Univ Fac Life Sci Dept Mol Psychol Rudower Chaussee 18 D-12489 Berlin Germany Heinrich Heine Univ Dusseldorf Inst Syst Neurosci Med Fac Dusseldorf Germany Inst Neurosci & Med INM 7 Brain & Behav Res Ctr Julich Julich Germany

The human thalamus relays sensory signals to the cortex and facilitates brain-wide communication. The thalamus is also more directly involved in sensorimotor and various cognitive functions but a full characterization of its functional repertoire, particularly in regard to its internal anatomical structure, is still outstanding. As a putative hub in the human connectome, the thalamus might reveal its functional profile only in conjunction with interconnected brain areas. We therefore developed a novel systems-level Bayesian reverse inference decoding that complements the traditional neuroinformatics approach towards a network account of thalamic function. The systems-level decoding considers the functional repertoire (i.e., the terms associated with a brain region) of all regions showing co-activations with a predefined seed region in a brain-wide fashion. Here, we used task-constrained meta-analytic connectivity-based parcellation (MACM-CBP) to identify thalamic subregions as seed regions and applied the systems-level decoding to these subregions in conjunction with functionally connected cortical regions. Our results confirm thalamic structure-function relationships known from animal and clinical studies and revealed further associations with language, memory, and locomotion that have not been detailed in the cognitive neuroscience literature before. The systems-level decoding further uncovered large systems engaged in autobiographical memory and nociception. We propose this novel decoding approach as a useful tool to detect previously unknown structure-function relationships at the brain network level, and to build viable starting points for future studies.

关键词： Thalamus Systems-level decoding structure-function relationships BrainMap database ALE meta-analysis Neurosynth

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Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug-Resistant Staphylococcus aureus: Insights from structure-function Analysis of Naphthoquinones

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CHEMMEDCHEM 2023年第24期18卷 e202300328页

作者： Mone, Nishigandha S. Syed, Sahil Ravichandiran, Palanisamy Kamble, Ekta E. Pardesi, Karishma R. Salunke-Gawali, Sunita Rai, Mansi Singh, Ajay Vikram Dakua, Sarada Prasad Park, Byung-Hyun Yoo, Dong Jin Satpute, Surekha K. Savitribai Phule Pune Univ Dept Microbiol Pune 411007 Maharashtra India Jeonbuk Natl Univ Grad Sch Hydrogen & Fuel Cell Res Ctr Dept Energy Storage Convers Engn BK21 FOUR Jeonju 54896 Jeollabuk Do South Korea Jeonbuk Natl Univ Dept Life Sci Jeonju 54896 Jeollabuk Do South Korea Savitribai Phule Pune Univ Dept Chem Pune 411007 Maharashtra India Cent Univ Rajasthan Dept Microbiol Ajmer 305817 Rajasthan India German Fed Inst BfR Dept Chem & Prod Safety Max Dohrn Str 8-10 D-10589 Berlin Germany Hamad Med Corp HMC Dept Surg Doha 3050 Qatar Jeonbuk Natl Univ Med Sch Dept Biochem 567 Baekje Daero Jeonju Si 54896 Jeollabuk Do South Korea

Antimicrobial resistance (AMR) interferes with the effective treatment of infections and increases the risk of microbial spread and infection-related illness and death. The synergistic activities of combinations of antimicrobial compounds offer satisfactory approaches to some extent. Structurally diverse naphthoquinones (NQs) including menadione (-CH3 group at C2) exhibit substantial antimicrobial activities against multidrug-resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against Staphylococcus aureus and its biofilms. We found an additive (0.590 %) were also observed. However, preformed biofilms were not affected. Dent formation was also evident in S. aureus treated with the test compounds. The structure-function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with -Cl, -Br, -CH3, or -OH groups displayed the lowest MICs (32-256 mu g/mL). Furthermore, 1,4-NQs possessing a halogen or -CH3 moiety showed elevated ROS activity, whereas molecules with an -OH group affected cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.

关键词： Antimicrobial resistance menadione naphthoquinones reactive oxygen species structure-function relationships

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The structural basis for the broad aldehyde specificity of the aminoaldehyde dehydrogenase PauC from the human pathogen Pseudomonas aeruginosa

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PROTEIN SCIENCE 2025年第5期34卷 e70124页

作者： Cardona-Cardona, Yudy V. Gonzalez-Segura, Lilian Rodriguez-Sotres, Rogelio Juarez-Diaz, Javier Andres Mujica-Jimenez, Carlos Regla, Ignacio Lopez-Ortiz, Manuel Munoz-Clares, Rosario A. Univ Nacl Autonoma Mexico Fac Quim Dept Bioquim Ciudad De Mexico 04510 Mexico Univ Nacl Autonoma Mexico Fac Ciencias Dept Biol Celular Ciudad De Mexico Mexico Univ Nacl Autonoma Mexico FES Zaragoza Ciudad De Mexico Mexico Univ Icesi Fac Ingn Diseno & Ciencias Aplicadas Dept Ciencias Farmaceut & Quim Cali Colombia

Despite significant differences in size and formal charge, the aldehyde dehydrogenase PaPauC (PA5312) from Pseudomonas aeruginosa PAO1 efficiently catalyzes the NAD+-dependent oxidation of the aminoaldehydes formed in polyamines degradation. We report here that PaPauC also oxidizes 4-guanidinebutyraldehyde, formed in one arginine degradation pathway, trimethylaminobutyraldehyde, of unknown metabolic origin, and indole-3-acetaldehyde, a precursor of the plant growth-promoting hormone indoleacetic acid. PaPauC has been proposed as a potential target for combating P. aeruginosa. However, understanding its structure-function relationships, crucial for developing specific inhibitors, is lacking. Using X-ray crystallography, we identified the structural characteristics that determine PaPauC broad aldehyde specificity: a spacious aldehyde-entrance tunnel and six active-site residues. Docking simulations, site-directed mutagenesis, and kinetic analyses support the interactions of Lys479 with glutamylated aminoaldehydes;Phe169, Trp176, and Phe467 with amino and guanidinium groups through cation-pi interactions and with the indole group via NH-pi and CH-pi interactions;Asp459 with amino and indole groups;and Thr303 with amide and guanidinium groups. Exploiting the distinctive structural features of the PaPauC active site could aid in developing specific inhibitors to combat P. aeruginosa infections in humans and animals, as well as in preventing its colonization of plants, which are abundant P. aeruginosa reservoirs and, therefore, a significant source of human infections.

关键词： amino aldehydes and indole-3-acetaldehyde oxidation molecular docking P. aeruginosa pathogenicity site-directed mutagenesis structure-function relationships X-ray protein structure

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structure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venom

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CELL REPORTS PHYSICAL SCIENCE 2023年第7期4卷 101459页

作者： Boaro, Andreia Ageitos, Lucia Torres, Marcelo Der Torossian Blasco, Esther Broset Oztekin, Sebahat de la Fuente-Nunez, Cesar Univ Penn Inst Biomed InformatDept Psychiat & Microbiol Inst Translat Med & Therapeut Perelman Sch MedMachine Biol Grp Philadelphia PA 19104 USA Univ Penn Sch Engn & Appl Sci Dept Bioengn & Chem & Biomol Engn Philadelphia PA 19104 USA Univ Penn Penn Inst Computat Sci Philadelphia PA 19104 USA Univ Fed ABC Ctr Ciencias Nat & Humanas BR-09210580 Santo Andre Brazil Univ A Coruna CICA Ctr Interdisciplinar Quim & Biol Dept Quim Fac Ciencias La Coruna 15008 Spain Bayburt Univ Fac Engn Dept Food Engn TR-69000 Bayburt Turkiye

Antimicrobial peptides (AMPs) derived from natural toxins and venoms offer a promising alternative source of antibiotics. Here, through structure-function-guided design, we convert two natural AMPs derived from the venom of the solitary eumenine wasp Eu-menes micado into a-helical AMPs with reduced toxicity that kill Gram-negative bacteria in vitro and in a preclinical mouse model. To identify the sequence determinants conferring antimicrobial ac-tivity, an alanine scan screen and strategic single lysine substitutions are made to the amino acid sequence of these natural peptides. These efforts yield a total of 34 synthetic derivatives, including alanine substituted and lysine-substituted sequences with stabilized a-helical structures and increased net positive charge. The resulting lead synthetic peptides kill the Gram-negative pathogens Escheri-chia coli and Pseudomonas aeruginosa (PAO1 and PA14) by rapidly permeabilizing both their outer and cytoplasmic membranes, exhibit anti-infective efficacy in a mouse model by reducing bacte-rial loads by up to three orders of magnitude, and do not readily select for bacterial resistance.

关键词： venoms antibiotics antimicrobial peptides synthetic peptides structure-function-guided design structure-function relationships bacterial resistance mechanism of action anti-infective activity mouse model

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Efficient polyethylene terephthalate degradation at moderate temperature: a protein engineering study of LC-cutinase highlights the key role of residue 243

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FEBS JOURNAL 2023年第12期290卷 3185-3202页

作者： Pirillo, Valentina Orlando, Marco Battaglia, Caren Pollegioni, Loredano Molla, Gianluca Univ Insubria Dept Biotechnol & Life Sci DBSV Varese Italy Univ Insubria Dept Biotechnol & Life Sci DBSV ViaJ H Dunant 3 I-21100 Varese Italy Univ Milano Bicocca Dept Biotechnol & Biosci BtBs Piazza Sci 2 I-20126 Milan Italy

Enzymatic degradation of poly(ethylene terephthalate) (PET) is becoming a reality because of the identification of novel PET-hydrolysing enzymes (PHEs) and the engineering of evolved enzyme variants. Here, improved variants of leaf-branch compost cutinase (LCC), a thermostable enzyme isolated by a metagenomic approach, were generated by a semi-rational protein engineering approach. Starting from a deleted LCC form lacking the secretion signal (Delta LCC), single and double variants possessing a higher activity on PET were isolated. The single-point F243T Delta LCC variant partially (similar to 67%) depolymerized amorphous PET film producing similar to 21.9 mm of products after 27 h of reaction at 72 degrees C. The S101N/F243T Delta LCC double variant reached a further increase in activity on PET. Notably, for both single and double variants the highest conversion yield was obtained at 55 degrees C. Kinetics studies and molecular dynamics simulations support that a slight decreased affinity for PET is responsible for the superior degradation performance of the S101N/F243T variant and that this stems from a slightly higher flexibility of the active site region close to position 243. Furthermore, our findings question the need for a high reaction temperature for PET degradation, at least for LCC: at >= 70 degrees C, the conversion of amorphous PET into a more crystalline polymer, resistant to enzymatic hydrolysis, is favoured. The evolved S101N/F243T Delta LCC variant is able to depolymerize fully 1.3 g of untreated postconsumer PET waste in <= 3 days at 55 degrees C (using 1.25 mg of enzyme only), this making PET enzymatic degradation by engineering LCC a more ecofriendly and sustainable process.

关键词： green technology improved LCC polyethylene terephthalate biodegradation rational design structure-function relationships

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