Discovery of a new class of type 1 methionine aminopeptidases that have relaxed substrate specificity

Bala, Sandeep Chowdary; Haque, Neshatul; Pillalamarri, Vijaykumar; Reddi, Ravikumar; Kashyap, R. P.; Marapaka, Anil Kumar; Addlagatta, A.

doi:10.1016/j.ijbiomac.2019.02.055

Cited by 8 publications

(4 citation statements)

References 31 publications

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“…Although MetAP2 is known to be involved in the development of specific tissues in multi-cellular organisms, the physiological role of MetAP1 has not been thoroughly studied [ 66 , 67 ], with reported results primarily as an antimicrobial target site [ 68 ]. A recent study has shown that certain proteins involved in lipid metabolism, cytoskeletal tissue, cell proliferation, and protein synthesis are differentially expressed in the protein group and transcriptome when MetAP1 activity is disrupted [ 69 ]. Although the MetAP1 gene serves a number of functions, its complete functions remain unknown.…”

Section: Discussionmentioning

confidence: 99%

The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance

Xiong

Dong

et al. 2022

IJMS

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Methionine aminopeptidases (MetAPs) catalyze the cleavage of the N-terminal initiator methionine (iMet) in new peptide chains and arylamides, which is essential for protein and peptide synthesis. MetAP is differentially expressed in two diamondback moth (DBM; Plutella xylostella) strains: the G88 susceptible strain and the Cry1S1000 strain, which are resistant to the Bt toxin Cry1Ac, implicating that MetAP expression might be associated with Bt resistance. In this study, we identified and cloned a MetAP gene from DBMs, named PxMetAP1, which has a CDS of 1140 bp and encodes a 379 amino acid protein. The relative expression of PxMetAP1 was found to be ~2.2-fold lower in the Cry1S1000 strain compared to that in the G88 strain. PxMetAP1 presents a stage- and tissue-specific expression pattern, with higher levels in the eggs, adults, integument, and fatbody of DBMs. The linkage between PxMetAP1 and Cry1Ac resistance is verified by genetic linkage analysis. The knockout of PxMetAP1 in G88 by CRISPR/Cas9 leads to a ~5.6-fold decrease in sensitivity to the Cry1Ac toxin, further supporting the association between the PxMetAP1 gene and Bt tolerance. Our research sheds light on the role of MetAP genes in the development of Bt tolerance in P. xylostella and enriches the knowledge for the management of such a cosmopolitan pest.

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Section: Discussionmentioning

confidence: 99%

The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance

Xiong

Dong

et al. 2022

IJMS

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“…To address the issues of bioavailability and solubility associated with resveratrol as an anti-obesity agent, Wan and colleagues formulated PLGA nanoparticles encapsulating resveratrol [51,52]. These nanoparticles were crafted using an oil-in-water emulsion method, yielding particles sized at 176.1 nm with a zeta potential of -22.6 mV.…”

Section: Drug Delivery Approaches For Bioactive Compounds In the Trea...mentioning

confidence: 99%

Advancements in Drug Delivery Systems for Natural Compounds Targeting Metabolic Disorders Associated with Inflammation

Sam,

Neal

2023

Arch Gastroenterol Res

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The global incidence of metabolic disorders is on the rise, posing a significant challenge to public health. With remarkable advancements in diagnostic tools and clinical procedures, our understanding of the etiology and underlying pathophysiology of these disorders has expanded considerably. Furthermore, the utilization of in vitro and in vivo experimental models, preceding clinical investigations, has catalyzed numerous breakthroughs in biomedicine, particularly in the identification and development of potential drug candidates for the management of metabolic disorders. Natural compounds isolated from various sources have garnered extensive attention as prospective drug candidates for the treatment of conditions such as diabetes, obesity, heart-related diseases, and cancer. This interest is partly attributed to their inherent antioxidant and anti-inflammatory properties. Concurrently, intensive research efforts have been directed towards enhancing the bioactivity and bioavailability of these compounds through selected drug delivery strategies. In this article, we provide valuable insights into recent advancements that shed light on the role of inflammatory-mediated responses in the initiation of metabolic disorders, with a specific focus on conditions like diabetes mellitus, obesity, heart-related diseases, cancer, and related drug delivery systems. Additionally, we explore the promising potential of natural products in managing these metabolic disorders. Furthermore, we present lists of potential biological targets suitable for high throughput screening in the drug discovery and development process. Finally, we delve into the findings gleaned from preclinical and clinical studies, setting the stage for the identification of suitable approaches in the realm of phytochemical drug delivery systems that hold promise for the treatment of metabolic disorders.

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“…There are two types of MetAP, MetAP1 and MetAP2, and the difference between both classes lies in the presence of an inserted internal polypeptide in the catalytic domain sequence of MetAP2 [19]. MetAP1 has four subtypes, i.e., 1a, 1b, 1c, 1d, and 1n [20,21]. MetAP1b and MetAP1c are distinguished from MetAP1a by the presence of N-terminal extension in the subtypes.…”

Section: Introductionmentioning

confidence: 99%

Anti-Tuberculosis Potential of OJT008 against Active and Multi-Drug-Resistant Mycobacterium Tuberculosis: In Silico and In Vitro Inhibition of Methionine Aminopeptidase

Onyenaka,

Idowu,

et al. 2023

IJMS

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Despite the recent progress in the diagnosis of tuberculosis (TB), the chemotherapeutic management of TB continues to be challenging. Mycobacterium tuberculosis (Mtb), the etiological agent of TB, is classified as the 13th leading cause of death globally. In addition, 450,000 people were reported to develop multi-drug-resistant TB globally. The current project focuses on targeting methionine aminopeptidase (MetAP), an essential protein for the viability of Mtb. MetAP is a metalloprotease that catalyzes the excision of the N-terminal methionine (NME) during protein synthesis, allowing the enzyme to be an auspicious target for the development of novel therapeutic agents for the treatment of TB. Mtb possesses two MetAP1 isoforms, MtMetAP1a and MtMetAP1c, which are vital for Mtb viability and, hence, a promising chemotherapeutic target for Mtb therapy. In this study, we cloned and overexpressed recombinant MtMetAP1c. We investigated the in vitro inhibitory effect of the novel MetAP inhibitor, OJT008, on the cobalt ion- and nickel ion-activated MtMetAP1c, and the mechanism of action was elucidated through an in silico approach. The compound’s potency against replicating and multi-drug-resistant (MDR) Mtb strains was also investigated. The induction of the overexpressed recombinant MtMetAP1c was optimized at 8 h with a final concentration of 1 mM Isopropyl β-D-1-thiogalactopyranoside. The average yield from 1 L of Escherichia coli culture for MtMetAP1c was 4.65 mg. A preliminary MtMetAP1c metal dependency screen showed optimum activation with nickel and cobalt ions occurred at 100 µM. The half-maximal inhibitory concentration (IC50) values of OJT008 against MtMetAP1c activated with CoCl2 and NiCl2 were 11 µM and 40 µM, respectively. The in silico study showed OJT008 strongly binds to both metal-activated MtMetAP1c, as evidenced by strong molecular interactions and a higher binding score, thereby corroborating our result. This in silico study validated the pharmacophore’s metal specificity. The potency of OJT008 against both active and MDR Mtb was <0.063 µg/mL. Our study reports OJT008 as an inhibitor of MtMetAP1c, which is potent at low micromolar concentrations against both active susceptible and MDR Mtb. These results suggest OJT008 is a potential lead compound for the development of novel small molecules for the therapeutic management of TB.

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Discovery of a new class of type 1 methionine aminopeptidases that have relaxed substrate specificity

Cited by 8 publications

References 31 publications

The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance

The Potential Role of the Methionine Aminopeptidase Gene PxMetAP1 in a Cosmopolitan Pest for Bacillus thuringiensis Toxin Tolerance

Advancements in Drug Delivery Systems for Natural Compounds Targeting Metabolic Disorders Associated with Inflammation

Anti-Tuberculosis Potential of OJT008 against Active and Multi-Drug-Resistant Mycobacterium Tuberculosis: In Silico and In Vitro Inhibition of Methionine Aminopeptidase

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