Last update 01 Nov 2024

MMAB

Last update 01 Nov 2024

Basic Info

Synonyms

ATP:co(I)rrinoid adenosyltransferase MMAB, cblB, CFAP23

+ [8]

Introduction

Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion (PubMed:12514191). Generates adenosylcobalamin (AdoCbl) and directly delivers the cofactor to MUT in a transfer that is stimulated by ATP-binding to MMAB and gated by MMAA (Probable).

Drugs associated with MMAB

AAV9-MMAB (NIH/NCATS)

Target

MMAB

Mechanism

MMAB modulators

Active Org.

National Institutes of Health [+1]

Originator Org.

National Center for Advancing Translational Sciences [+1]

Active Indication

Methylmalonic Acidemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MMAB

100 Translational Medicine associated with MMAB

0 Patents (Medical) associated with MMAB

Literatures (Medical) associated with MMAB

06 Aug 2024·Biochemistry

A Noble Metal Substitution Leads to B₁₂ Cofactor Mimicry by a Rhodibalamin

Article

Author: Krautler, Bernhard ; Mascarenhas, Romila ; Widner, Florian ; Banerjee, Ruma ; Ruetz, Markus ; Kieninger, Christoph ; Koutmos, Markos

In mammals, cobalamin is an essential cofactor that is delivered by a multitude of chaperones in an elaborate trafficking pathway to two client enzymes, methionine synthase and methylmalonyl-CoA mutase (MMUT). Rhodibalamins, the rhodium analogs of cobalamins, have been described as antimetabolites due to their ability to inhibit bacterial growth. In this study, we have examined the reactivity of adenosylrhodibalamin (AdoRhbl) with two key human chaperones, MMACHC (also known as CblC) and adenosyltransferase (MMAB, also known as ATR), and with the human and Mycobacterium tuberculosis MMUT. We demonstrate that while AdoRhbl binds tightly to all four proteins, the Rh-carbon bond is resistant to homolytic (on MMAB and MMUT) as well as heterolytic (on MMACHC) rupture. On the other hand, MMAB catalyzes Rh-carbon bond formation, converting rhodi(I)balamin in the presence of ATP to AdoRhbl. We report the first crystal structure of a rhodibalamin (AdoRhbl) bound to a B₁₂ protein, i.e., MMAB, in the presence of triphosphate, which shows a weakened but intact Rh-carbon bond. The structure provides insights into how MMAB cleaves the corresponding Co-carbon bond in a sacrificial homolytic reaction that purportedly functions as a cofactor sequestration strategy. Collectively, the study demonstrates that while the noble metal substitution of cobalt by rhodium sets up structural mimicry, it compromises chemistry, which could be exploited for targeting human and bacterial B₁₂ chaperones and enzymes.

31 Oct 2023·Cureus

Methylmalonyl Coenzyme A (CoA) Epimerase Deficiency, an Ultra-Rare Cause of Isolated Methylmalonic Aciduria With Predominant Neurological Features

Author: Rua, Inês B ; Pereira, Cristina ; Diogo, Rui ; Ferreira, Sara ; Rosmaninho-Salgado, Joana ; Diogo, Luísa ; Nogueira, Célia

Methylmalonyl coenzyme A (CoA) epimerase (MCE) converts D-methylmalonyl-CoA into L-methylmalonyl CoA in the final common degradation pathway of valine, isoleucine, methionine, threonine, odd-chain fatty acids, and cholesterol side chains. Methylmalonyl-CoA epimerase deficiency is an ultra-rare autosomal recessive disorder where methylmalonic acid, methylcitrate, 3-hydroxypropionate, and propionylcarnitine are accumulated. We describe two novel pediatric patients and review the previously reported cases of MCE deficiency. Including our two novel patients, at least 24 cases of MCE deficiency have been described, with a broad clinical spectrum ranging from asymptomatic to severely neurologically impaired patients. Our patients are siblings of Arabic origin who presented with metabolic decompensation with coma and epilepsy during infancy. Methylmalonic aciduria was disclosed, L-methylmalonyl-CoA mutase deficiency was assumed, and they were treated accordingly. When first seen in our country, aged 10 and four years, respectively, both presented severe intellectual disability and spasticity. The younger had an ataxic gait, and the older was wheelchair-ridden. The study of the MMUT, MMAA, MMAB, and MMADHC genes was normal. Subsequently, the pathogenic variant c.139C>T (p.Arg47*) in the MCEE gene was identified in homozygosity in both patients, leading to the diagnosis of MCE deficiency (Online Mendelian Inheritance in Man (OMIM^®) 251120, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, MD, USA). Most patients were homozygous for that variant (83% of the alleles). Correct diagnosis allowed treatment adequacy and genetic counseling. Methylmalonyl-CoA epimerase deficiency shares a similar biochemical profile with other rare genetic disorders. Patients present with overlapping clinical features with predominant neurological manifestations; genetic testing is indispensable for diagnosis. We found no association between genotype and biochemical and clinical phenotypes.

14 Aug 2023·Inorganic chemistry

Coordination Chemistry Controls Coenzyme B₁₂ Synthesis by Human Adenosine Triphosphate:Cob(I)alamin Adenosyltransferase.

Article

Author: Ruetz, Markus ; Gouda, Harsha ; Banerjee, Ruma ; Li, Zhu

Cobalamin (or vitamin B₁₂)-dependent enzymes and trafficking chaperones exploit redox-linked coordination chemistry to control the cofactor reactivity during catalysis and translocation. As the cobalt oxidation state decreases from 3+ to 1+, the preferred cobalamin geometry changes from six- to four-coordinate (4-c). In this study, we reveal the sizable thermodynamic gain that accrues for human adenosine triphosphate (ATP):cob(I)alamin adenosyltransferase (or MMAB) by enforcing an unfavorable 4-c cob(II)alamin geometry. MMAB-bound cob(II)alamin is reduced to the supernucleophilic cob(I)alamin intermediate during the synthesis of 5'-deoxyadenosylcobalamin. Herein, we report the first experimentally determined reduction potential for 4-c cob(II)alamin (-325 ± 9 mV), which is 180 mV more positive than for the five-coordinate (5-c) water-liganded species. The redox potential of MMAB-bound cob(II)alamin is within the range of adrenodoxin, which we demonstrate functions as an electron donor. We also show that stabilization of 5-c cob(II)alamin by a subset of MMAB patient variants compromises the reduction by adrenodoxin, explaining the underlying pathogenic mechanism.

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