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Targeting of Functional Proteins in Disease Therapeutics: Enzyme Function and Inhibition Studies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 September 2024 | Viewed by 3673

Special Issue Editor

Prof. Dr. Sung-Kun (Sean) Kim

E-Mail Website
Guest Editor
Department of Natural Sciences, Northeastern State University, Broken Arrow, OK 74014, USA
Interests: biochemistry; enzymology; drug discovery; SELEX (systematic evolution of ligands by exponential enrichment); in vitro selection technique
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Enzymes emerge as pivotal keystones in drug development across the pharmaceutical landscape. Unraveling the intricate tapestry of enzymatic entities is vital to decoding their multifaceted reactions. A plethora of analytical methodologies converge, orchestrating a comprehensive characterization journey that encompasses purification paradigms, kinetics dissection, protein stabilization methodologies, and the optimization of pivotal parameters spanning pH, temperature, and ionic strength. The quest extends to encompass the exhaustive elucidation of substrate–product binding dynamics, intricate voyages into ligand/inhibitor/protein interplays, unveiling the troves of three-dimensional structural nuances, and navigating the transformative contours of conformational variations.

A recent seismic shift has occurred with the advent of in silico analysis, catalyzing an epochal leap in the realm of enzyme characterization. The symphony of molecular docking and molecular dynamics orchestrates a pivotal melody, propelling this transformative trajectory. This illustrious Special Issue serves as an intellectual crucible, amalgamating an eclectic symposium of captivating themes, igniting a symphony of ideas, and propelling the discourse towards enzymes and proteins as potent bull's-eyes within the drug development panorama.

Encompassing the following trajectories, this Special Issue embarks upon a profound odyssey:

  1. Pioneering Inhibition Frontiers: Forging Novel Inhibitors to Tame the Vigor of Enzymatic Domains
  2. The Mechanistic Odyssey: Immersion into the Innate Functional Machinery of Enzymatic Realms
  3. Metamorphosis of Enzyme Conformation: Navigating the Dynamic Cartography of Catalytic Architecture
  4. Unveiling Ligand Precision through Multidimensional Play: Convergence of In Vitro and In Silico Vistas

Prof. Dr. Sung-Kun (Sean) Kim
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enzymes
  • disease therapeutics
  • inhibitior

Published Papers (4 papers)

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Research

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12 pages, 4102 KiB  
Communication
Discovering New Substrates of a UDP-Glycosyltransferase with a High-Throughput Method
by Mary C. L. Lethe, Dinh Bui, Ming Hu, Xiaoqiang Wang, Rashim Singh and Clement T. Y. Chan
Int. J. Mol. Sci. 2024, 25(5), 2725; https://doi.org/10.3390/ijms25052725 - 27 Feb 2024
Viewed by 843
Abstract
UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of substrates, and they derivatize xenobiotics and metabolites for detoxification. However, most UGT homologs have not been well [...] Read more.
UDP-glycosyltransferases (UGTs) form a large enzyme family that is found in a wide range of organisms. These enzymes are known for accepting a wide variety of substrates, and they derivatize xenobiotics and metabolites for detoxification. However, most UGT homologs have not been well characterized, and their potential for biomedical and environmental applications is underexplored. In this work, we have used a fluorescent assay for screening substrates of a plant UGT homolog by monitoring the formation of UDP. We optimized the assay such that it could be used for high-throughput screening of substrates of the Medicago truncatula UGT enzyme, UGT71G1, and our results show that 34 of the 159 screened compound samples are potential substrates. With an LC–MS/MS method, we confirmed that three of these candidates indeed were glycosylated by UGT71G1, which includes bisphenol A (BPA) and 7-Ethyl-10-hydroxycamptothecin (SN-38); derivatization of these toxic compounds can lead to new environmental and medical applications. This work suggests that UGT homologs may recognize a substrate profile that is much broader than previously anticipated. Additionally, it demonstrates that this screening method provides a new means to study UDP-glycosyltransferases, facilitating the use of these enzymes to tackle a wide range of problems. Full article
(This article belongs to the Special Issue Targeting of Functional Proteins in Disease Therapeutics: Enzyme Function and Inhibition Studies)
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14 pages, 969 KiB  
Article
A Simple, Fast, Sensitive LC-MS/MS Method to Quantify NAD(H) in Biological Samples: Plasma NAD(H) Measurement to Monitor Brain Pathophysiology
by Tamaki Ishima, Natsuka Kimura, Mizuki Kobayashi, Ryozo Nagai, Hitoshi Osaka and Kenichi Aizawa
Int. J. Mol. Sci. 2024, 25(4), 2325; https://doi.org/10.3390/ijms25042325 - 15 Feb 2024
Viewed by 955
Abstract
Nicotinamide adenine dinucleotide (NAD) is a cofactor in redox reactions and an essential mediator of energy metabolism. The redox balance between NAD+ and NADH affects various diseases, cell differentiation, and aging, and in recent years there has been a growing need for [...] Read more.
Nicotinamide adenine dinucleotide (NAD) is a cofactor in redox reactions and an essential mediator of energy metabolism. The redox balance between NAD+ and NADH affects various diseases, cell differentiation, and aging, and in recent years there has been a growing need for measurement techniques with improved accuracy. However, NAD(H) measurements, representing both NAD+ and NADH, have been limited by the compound’s properties. We achieved highly sensitive simultaneous measurement of NAD+ and NADH under non-ion pairing, mobile phase conditions of water, or methanol containing 5 mM ammonium acetate. These were achieved using a simple pre-treatment and 7-min analysis time. Use of the stable isotope 13C5-NAD+ as an internal standard enabled validation close to BMV criteria and demonstrated the robustness of NAD(H) determination. Measurements using this method showed that brain NAD(H) levels correlate strongly with plasma NAD(H) levels in the same mouse, indicating that NAD(H) concentrations in brain tissue are reflected in plasma. As NAD(H) is involved in various neurodegenerative diseases and cerebral ischemia, as well as brain diseases such as mitochondrial myopathies, monitoring changes in NADH levels in plasma after drug administration will be useful for development of future diagnostics and therapeutics. Full article
(This article belongs to the Special Issue Targeting of Functional Proteins in Disease Therapeutics: Enzyme Function and Inhibition Studies)
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Review

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17 pages, 1816 KiB  
Review
Unravelling the Intricate Roles of FAM111A and FAM111B: From Protease-Mediated Cellular Processes to Disease Implications
by Danielle Naicker, Cenza Rhoda, Falone Sunda and Afolake Arowolo
Int. J. Mol. Sci. 2024, 25(5), 2845; https://doi.org/10.3390/ijms25052845 - 29 Feb 2024
Viewed by 766
Abstract
Proteases are critical enzymes in cellular processes which regulate intricate events like cellular proliferation, differentiation and apoptosis. This review highlights the multifaceted roles of the serine proteases FAM111A and FAM111B, exploring their impact on cellular functions and diseases. FAM111A is implicated in DNA [...] Read more.
Proteases are critical enzymes in cellular processes which regulate intricate events like cellular proliferation, differentiation and apoptosis. This review highlights the multifaceted roles of the serine proteases FAM111A and FAM111B, exploring their impact on cellular functions and diseases. FAM111A is implicated in DNA replication and replication fork protection, thereby maintaining genome integrity. Additionally, FAM111A functions as an antiviral factor against DNA and RNA viruses. Apart from being involved in DNA repair, FAM111B, a paralog of FAM111A, participates in cell cycle regulation and apoptosis. It influences the apoptotic pathway by upregulating anti-apoptotic proteins and modulating cell cycle-related proteins. Furthermore, FAM111B’s association with nucleoporins suggests its involvement in nucleo-cytoplasmic trafficking and plays a role in maintaining normal telomere length. FAM111A and FAM111B also exhibit some interconnectedness and functional similarity despite their distinct roles in cellular processes and associated diseases resulting from their dysfunction. FAM111A and FAM111B dysregulation are linked to genetic disorders: Kenny–Caffey Syndrome type 2 and Gracile Bone Dysplasia for FAM111A and POIKTMP, respectively, and cancers. Therefore, the dysregulation of these proteases in diseases emphasizes their potential as diagnostic markers and therapeutic targets. Future research is essential to unravel the intricate mechanisms governing FAM111A and FAM111B and explore their therapeutic implications comprehensively. Full article
(This article belongs to the Special Issue Targeting of Functional Proteins in Disease Therapeutics: Enzyme Function and Inhibition Studies)
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16 pages, 5402 KiB  
Review
Similarities in Structure and Function of UDP-Glycosyltransferase Homologs from Human and Plants
by Mary Caroline L. Lethe, Vincent Paris, Xiaoqiang Wang and Clement T. Y. Chan
Int. J. Mol. Sci. 2024, 25(5), 2782; https://doi.org/10.3390/ijms25052782 - 28 Feb 2024
Viewed by 719
Abstract
The uridine diphosphate glycosyltransferase (UGT) superfamily plays a key role in the metabolism of xenobiotics and metabolic wastes, which is essential for detoxifying those species. Over the last several decades, a huge effort has been put into studying human and mammalian UGT homologs, [...] Read more.
The uridine diphosphate glycosyltransferase (UGT) superfamily plays a key role in the metabolism of xenobiotics and metabolic wastes, which is essential for detoxifying those species. Over the last several decades, a huge effort has been put into studying human and mammalian UGT homologs, but family members in other organisms have been explored much less. Potentially, other UGT homologs can have desirable substrate specificity and biological activities that can be harnessed for detoxification in various medical settings. In this review article, we take a plant UGT homology, UGT71G1, and compare its structural and biochemical properties with the human homologs. These comparisons suggest that even though mammalian and plant UGTs are functional in different environments, they may support similar biochemical activities based on their protein structure and function. The known biological functions of these homologs are discussed so as to provide insights into the use of UGT homologs from other organisms for addressing human diseases related to UGTs. Full article
(This article belongs to the Special Issue Targeting of Functional Proteins in Disease Therapeutics: Enzyme Function and Inhibition Studies)
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