Human B12-dependent enzymes: Methionine synthase and Methylmalonyl-CoA mutase

Mascarenhas, Romila; Gouda, Harsha; Ruetz, Markus; Banerjee, Ruma

doi:10.1016/bs.mie.2021.12.012

Cited by 16 publications

(20 citation statements)

References 34 publications

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“…We focused our studies on the C-terminal half of human MTR, comprising the B 12 and AdoMet-binding domains (denoted hereafter as ΔN MTR, Figure 1B), due to the low soluble expression yield of full-length recombinant human MTR in E. coli or insect cells. 25 Addition of ΔN MTR to an anaerobic solution of cob(II)alamin elicited a blue shift from 474 to 470 nm (Figure S1A). ΔN MTR also bound MeCbl from solution but not OH 2 Cbl or glutathionyl cobalamin (GSCbl) (Figure S1B− D).…”

Section: ■ Resultsmentioning

confidence: 99%

“…Full-length human MTR was expressed in insect cells and purified as described previously. 25 Briefly, MTR cDNA was inserted into the pFastBac Dual LIC cloning vector with an N-terminal HisX 6 -tag, followed by a maltose-binding protein (MBP) tag and a TEV cleavage site between MBP and MTR. Hi5 insect cells were infected with recombinant baculovirus and incubated for 44 h at 27 °C and 110 rpm.…”

Section: ■ Methodsmentioning

confidence: 99%

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Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Mascarenhas,

Guha,

et al. 2023

J. Am. Chem. Soc.

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Cobalt−sulfur (Co−S) coordination is labile to both oxidation and reduction chemistry and is rarely seen in nature. Cobalamin (or vitamin B 12 ) is an essential cobalt-containing organometallic cofactor in mammals and is escorted via an intricate network of chaperones to a single cytoplasmic target, methionine synthase. In this study, we report that the human cobalamin trafficking protein, MMADHC, exploits the chemical lability of Co−S coordination for cofactor off-loading onto methionine synthase. Cys-261 on MMADHC serves as the β-axial ligand to cobalamin. Complex formation between MMADHC and methionine synthase is signaled by loss of the lower axial nitrogen ligand, leading to five-coordinate thiolato-cobalamin. Nucleophilic displacement by the vicinal thiolate, Cys-262, completes cofactor transfer to methionine synthase and release of a cysteine disulfide-containing MMADHC. The physiological relevance of this mechanism is supported by clinical variants of MMADHC, which impair cofactor binding and off-loading, explaining the molecular basis of the associated homocystinuria.

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Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Methodsmentioning

confidence: 99%

Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Mascarenhas,

Guha,

et al. 2023

J. Am. Chem. Soc.

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“…Vitamin B12 is the necessary co-factor for only two enzymatic reactions in human physiology [ 43 , 44 , 45 , 46 ]. Despite this, an incredibly broad array of symptoms can follow from B12 insufficiency.…”

Section: Question One: What Is Your Preferred Source Of Vitamin B12?mentioning

confidence: 99%

“…The first enzyme, methionine synthase, is crucial in the methylation cycle. Insufficient B12 in the methylcobalamin form results in elevated homocysteine and impairment of all methylation-dependent processes including [ 46 , 47 ]: Neurotransmitter metabolism (mood, energy, cognition); Estrogen metabolism (PMS, endometriosis, menstrual cycle irregularities); Histamine clearance (histamine intolerance); Phosphatidylcholine production (cell membrane composition and function, intestinal mucus, pulmonary surfactant); Creatine and carnitine production (cognition, strength/stamina, mood); Myelin production (neurologic, cognitive function); DNA synthesis. …”

Section: Question One: What Is Your Preferred Source Of Vitamin B12?mentioning

confidence: 99%

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Nutritional Assessment of the Symptomatic Patient on a Plant-Based Diet: Seven Key Questions

Plotnikoff¹,

Dobberstein²,

Raatz

2023

Nutrients

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Plant-based diets, both vegan and vegetarian, which emphasize grains, vegetables, fruits, legumes, nuts, and seeds are increasingly popular for health as well as financial, ethical, and religious reasons. The medical literature clearly demonstrates that whole food plant-based diets can be both nutritionally sufficient and medically beneficial. However, any person on an intentionally restrictive, but poorly-designed diet may predispose themselves to clinically-relevant nutritional deficiencies. For persons on a poorly-designed plant-based diet, deficiencies are possible in both macronutrients (protein, essential fatty acids) and micronutrients (vitamin B12, iron, calcium, zinc, and vitamin D). Practitioner evaluation of symptomatic patients on a plant-based diet requires special consideration of seven key nutrient concerns for plant-based diets. This article translates these concerns into seven practical questions that all practitioners can introduce into their patient assessments and clinical reasoning. Ideally, persons on plant-based diets should be able to answer these seven questions. Each serves as a heuristic prompt for both clinician and patient attentiveness to a complete diet. As such, these seven questions support increased patient nutrition knowledge and practitioner capacity to counsel, refer, and appropriately focus clinical resources.

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The effect of vitamin B12 on DNA adduction by styrene oxide, a genotoxic xenobiotic

Watson

Munter

Golding

2023

Chemico-Biological Interactions

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Human B12-dependent enzymes: Methionine synthase and Methylmalonyl-CoA mutase

Cited by 16 publications

References 34 publications

Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Nutritional Assessment of the Symptomatic Patient on a Plant-Based Diet: Seven Key Questions

The effect of vitamin B12 on DNA adduction by styrene oxide, a genotoxic xenobiotic

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Human B12-dependent enzymes: Methionine synthase and Methylmalonyl-CoA mutase

Cited by 16 publications

References 34 publications

Cobalt–Sulfur Coordination Chemistry Drives B12 Loading onto Methionine Synthase

Cobalt–Sulfur Coordination Chemistry Drives B12 Loading onto Methionine Synthase

Nutritional Assessment of the Symptomatic Patient on a Plant-Based Diet: Seven Key Questions

The effect of vitamin B12 on DNA adduction by styrene oxide, a genotoxic xenobiotic

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Product

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Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase

Cobalt–Sulfur Coordination Chemistry Drives B₁₂ Loading onto Methionine Synthase