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Methylmalonic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
All patients with methylmalonic acidemia have defective activity of methylmalonyl CoA mutase (Figure 3.1), the enzyme that catalyzes the conversion of methylmalonyl CoA to succinyl CoA (see Figure 2.1). This enzyme lies on the direct degradative pathway for isoleucine, valine, threonine, and methionine. All of these amino acids have been shown to be major sources of methylmalonate in patients. On the other hand, lipids, although metabolizable via this pathway, do not contribute in measurable fashion to urinary MMA [76].
Lysosomal Vitamin B12 Trafficking
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sean Froese, Matthias R. Baumgartner
Vitamin B12 (cobalamin, Cbl) is required as cofactor for two essential human enzymes: cytosolic methionine synthase and mitochondrial methylmalonyl-CoA mutase. In order to reach these destination enzymes in the correct cofactor forms, Cbl must be taken up, modified and transported across the cell (Figure 7.1). Cellular entry of Cbl occurs through receptor mediated endocytosis, by which Cbl bound to the carrier protein transcobalamin is recognized by its nascent receptor CD320 (also known as the transcobalamin receptor, TCblR). Following progressive acidification in the transition from early- to late-endosomes, and finally lysosomes, the engulfed transcobalamin is degraded and Cbl is released. Free Cbl is then exported from the lysosome into the cytosol, where a series of metabolic steps results in the production of methyl-Cbl, the cofactor form for methionine synthase, or in transport into the mitochondria and the conversion to adenosyl-Cbl, the cofactor form for methylmalonyl-CoA mutase. Methionine synthase (E.C. 2.1.1.13), as part of the methionine cycle, is responsible for the production of methionine and ultimately S-adenosylmethionine. Methylmalonyl-CoA mutase (E.C. 5.4.99.2), a component of the propionate catabolic pathway for branched-chain amino acids, odd-chain fatty acids and the side chain of cholesterol, funnels catabolic intermediates into the tricarboxylic acid cycle.
Vitamin Deficiency in Patients with Terminal Cancer
Published in Victor R. Preedy, Handbook of Nutrition and Diet in Palliative Care, 2019
Renata Gorska, Dominic J. Harrington
In humans the functions of two enzymes are dependent on vitamin B12: methylmalonyl-CoA mutase and methionine synthase. Methylmalonyl-CoA mutase vitamin converts methylmalonyl-CoA to succinyl-CoA. When the supply of of vitamin B12 is suboptimal, this reaction cannot proceed, leading to the increased formation of methylmalonic acid.
Oral vitamin B12 supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting Bacteroides in C57BL/6 mice
Published in Gut Microbes, 2019
Caleb J Kelly, Erica E Alexeev, Linda Farb, Thad W Vickery, Leon Zheng, Campbell Eric L, David A Kitzenberg, Kayla D Battista, Douglas J Kominsky, Charles E Robertson, Daniel N Frank, Sally P Stabler, Sean P Colgan
Two known B12-dependent enzymes have been described in humans, but at least 15 B12-dependent enzymes exist among gut microbes.8 B12 has additional roles in microbial gene regulation, functioning in B12-dependent riboswitches (regulatory RNA elements),9 and as a cofactor for gene regulatory proteins.10 L-Methylmalonyl-CoA mutase is a B12-dependent enzyme shared by humans and microbes (though the direction of product-substrate is reversed). Anaerobic microbes use this enzyme to generate CO2, a critical electron acceptor in the anaerobic lumen.11 Propionate, a short-chain fatty acid (SCFA) generated as a byproduct of this reaction, is important in host physiology and immunity.4,12 In one study, the addition of B12 to bacterial growth media increased propionate production by three bacterial species.13 This knowledge prompted the hypothesis that oral B12 might alter microbial SCFA production and thereby, resistance to colitis in the distal gut.
Optic neuropathy in classical methylmalonic acidemia
Published in Ophthalmic Genetics, 2019
Mohammed AlOwain, Ola Ali Khalifa, Zahra Al Sahlawi, Maged H Hussein, Raashda A Sulaiman, Moeen Al-Sayed, Zuhair Rahbeeni, Zuhair Al-Hassnan, Hamad Al-Zaidan, Hachemi Nezzar, Iftetah Al Homoud, Abdelmoneim Eldali, Brian Altonen, Bedour S Handoom, Joyce N Mbekeani
Methylmalonic acidemia (MMA) is a relatively common autosomal recessive-inherited metabolic disorder of branched-chain amino acids (isoleucine, valine, methionine and threonine), odd-chained fatty acids and cholesterol. Biochemically, methylmalonic acidemia (MMA, OMIM 609058) is the hallmark of a group of metabolic disorders that disturbs the conversion of methylmalonyl-CoA into succinyl-CoA. The classical form is a consequence of mutation of the MUT gene on chromosome 6, responsible for production of the mitochondrial, methylmalonyl CoA mutase apoenzyme (MCM, EC 5.4.99.2) (1–3). The resultant enzyme deficiency prevents vitamin B12-dependent conversion of methylmalonyl-CoA to succinyl-CoA, required in the Krebs cycle for energy production and the accumulation of methylmalonic acid in various tissues and body fluids. This metabolic disorder is characterized by intermittent periods of potentially lethal metabolic decompensation (metabolic acidosis and/or hyperammonemia), usually triggered by concurrent infection, dietary indiscretion and stress, followed by periods of relatively good clinical health (4,5). These episodes are defined as metabolic crises. Disorders of intracellular cobalamin metabolism caused by impaired synthesis or transport of the cofactor, adenosyl-cobalamin (cblA, cblB and variant 2 of cblD-MMA) exhibit phenotypically similar clinical features to MMA (1,3,4).
ZRSR2 mutation in a child with refractory macrocytic anemia and Down Syndrome
Published in Pediatric Hematology and Oncology, 2019
Meghna Srinath, Emily Coberly, Kimberly Ebersol, Kirstin Binz, Katsiaryna Laziuk, William T. Gunning, Barbara Gruner, Richard Hammer, Bindu Kanathezhath Sathi
Because of the megaloblastic picture, amino acid profiling was done which revealed elevated methylmalonic acid level (0.60 nmol mL−1 (<0.40)) with normal homocysteine. Intramuscular B12 and oral folate therapy was started, in addition to pRBC transfusion when Hb was persistently lower than 7 g dL−1. After 6 months of pRBC therapy, the frequency of transfusions increased with persistent normocytic-to-macrocytic anemia (MCV 83.7–95.3 fL) and low iron and ferritin despite continuous iron therapy. There was evidence of chronic fecal occult blood loss; however, a Meckel’s scan, upper and lower gut endoscopies, capsule studies, and RBC nuclear scan revealed only chronic gastritis with no active bleeding source. Absorption of oral iron was found to be normal and testing for pernicious anemia (anti-Intrinsic factor antibody) was negative. Testing for mutations in methylmalonyl-CoA mutase was negative, and the patient did not exhibit other features or symptoms of methylmalonyl-CoA mutase deficiency.