Last update 01 Nov 2024

MBLAC1

Last update 01 Nov 2024

Basic Info

Synonyms

Endoribonuclease MBLAC1, MBLAC1, metallo-beta-lactamase domain containing 1

+ [2]

Introduction

Endoribonuclease that catalyzes the hydrolysis of histone-coding pre-mRNA 3'-end. Involved in histone pre-mRNA processing during the S-phase of the cell cycle, which is required for entering/progressing through S-phase (PubMed:30507380). Cleaves histone pre-mRNA at a major and a minor cleavage site after the 5'-ACCCA-3' and the 5'-ACCCACA-3' sequence, respectively, and located downstream of the stem-loop (PubMed:30507380). May require the presence of the HDE element located at the histone pre-RNA 3'-end to avoid non-specific cleavage (PubMed:30507380).

Drugs associated with MBLAC1

Zndm19

Target

MBLAC1

Mechanism

MBLAC1 inhibitors

Active Org.

Jilin University

Originator Org.

Jilin University

Active Indication

Bacterial Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MBLAC1

100 Translational Medicine associated with MBLAC1

0 Patents (Medical) associated with MBLAC1

303

Literatures (Medical) associated with MBLAC1

24 Sep 2024·Proceedings of the National Academy of Sciences

Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis

Article

Author: Gichi, Zayna ; Chang, Christopher J. ; Xiao, Tong ; Gibson, Chelsea L. ; Boerner, Jana ; Carvelli, Lucia ; Kalia, Vrinda ; Fenollar-Ferrer, Cristina ; Blakely, Randy D. ; Rajoo, Andre ; Matier, Carson D. ; Khamoui, Andy V. ; Miller, Gary W. ; Rodriguez, Peter ; Pezacki, Aidan T.

Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson’s disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.

01 Aug 2024·Biochemical and Biophysical Research Communications

Structural insight into the subclass B1 metallo-β-lactamase AFM-1

Article

Author: Ti, Ruijiao ; Li, Dongxu ; Wang, Zefang ; Ye, Yiwen ; Dong, Ruihan ; Niu, Wenqian ; Dong, Jian ; Xiao, Yunjie

The emergence of drug-resistant bacteria, facilitated by metallo-beta-lactamases (MBLs), presents a significant obstacle to the effective use of antibiotics in the management of clinical drug-resistant bacterial infections. AFM-1 is a MBL derived from Alcaligenes faecalis and shares 86% homology with the NDM-1 family. Both AFM-1 and NDM-1 demonstrate the ability to hydrolyze ampicillin and other β-lactam antibiotics, however, their substrate affinities vary, and the specific reason for this variation remains unknown. We present the high-resolution structure of AFM-1. The active center of AFM-1 binds two zinc ions, and the conformation of the key amino acid residues in the active center is in accordance with that of NDM-1. However, the substrate-binding pocket of AFM-1 is considerably smaller than that of NDM-1. Additionally, the mutation of amino acid residues in the Loop3 region, as compared to NDM-1, results in the formation of a dense hydrophobic patch comprised of hydrophobic amino acid residues in this area, which facilitates substrate binding. Our findings lay the foundation for understanding the molecular mechanism of AFM-1 with a high affinity for substrates and provide a novel theoretical foundation for addressing the issue of drug resistance caused by B1 MBLs.

01 Jul 2024·Journal of Infection and Chemotherapy

Ceftazidime-avibactam in the treatment of bacteremia due to carbapenem-resistant gram-negative bacteria in hematological patients: Experience in a single center

Article

Author: Feng, Sizhou ; He, Yi ; Zhai, Weihua ; Pang, Aiming ; Wei, Jialin ; Han, Mingzhe ; Wang, Jianxiang ; Chen, Xin ; Zhang, Rongli ; Yang, Donglin ; Shen, Yuyan ; Zhen, Sisi ; Ma, Qiaoling ; Lin, Qingsong ; Jiang, Erlie ; Chen, Zhangjie

INTRODUCTIONLimited experience exists with ceftazidime-avibactam (CAZ-AVI) in treating bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients.METHODSWe performed a single-center, retrospective, observational study including patients who received CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. We conducted a multivariable analysis to identify predictors of survival.RESULTS56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase, including 25 metallo-beta-lactamase (MBL) and 10 serine-beta-lactamase. 48 patients (85.7 %) received combination therapy. All patients with MBL-CRE bacteremia (n = 24) received combination therapy with aztreonam (AZT). The susceptibility rates to CAZ-AVI were only 26.8 % (11/41) in CRE and 80.0 % (8/10) in CRPA. The 30-day survival rates were 85.0 % (34/40) in the CRE group and 81.3 % (13/16) in the CRPA group. In patients with MBL-CRE bacteremia, the 30-day survival was as high as 91.7 % (22/24) due to combination with AZT. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia >14 days (P = 0.002, HR: 34.483, 95%CI: 3.846-333.333) and a higher Pitt bacteremia score (P = 0.005, HR: 2.074, 95%CI: 1.253-3.436) were risk factors for 30-day survival.CONCLUSIONSCAZ-AVI is highly effective in treating bacteremia due to CRPA and serine-beta-lactamase CRE. The combination of avibactam with AZT is highly effective in treating bacteremia due to AZT-resistant MBL producers.

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MBLAC1

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