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Vitamin B12 stabilizes an mRNA regulatory switch

Humans need cobalamin (vitamin B12) for producing red blood cells and a healthy nervous system. Vitamin B12 is required in humans to produce healthy red blood cells in the bone marrow. Since vitamin B12 is only readily available in a human diet that consumes animal meats and dairy products or yeast extracts, modern humans may not get enough vitamin B12 from their diet. The human body metabolizes the water-soluble B vitamines very fast. Therefore, humans need to consume B vitamins daily. A diet supplemented with vitamin B12 will avoid a vitamin B12 deficiency; this is especially important for aging people. Therefore, older people and vegans may need vitamin B12 fortified foods or supplements to maintain a healthy vitamin B12 level in their blood.

Vitamin B12 is essential for folate metabolism and the synthesis of a citric acid cycle intermediate called succinyl-CoA. Vitamin B12 and folate are also crucial for homocysteine metabolism. To maintain the integrity of DNA, folate and vitamin B12 are needed.

In humans, vitamin B12 is a cofactor-precursor for two biochemical reactions. After ingestion, a multistep transport system transports cobalamins into the bloodstream. The soluble protein transcobalamin (TC) binds cobalamin. Next, receptor-mediated endocytosis transports the TC-cobalamin complex into the cell. Bloch et al., in 2017, studied the transportation complex assembly by solving four structures of the beta domain of human transcobalamin bound to different cyanocobalamin. Figure 1 shows structural models for transcobalamin-2 in complex with cobalt cyanocobalamin.  


Figure 1: Beta domain of human transcobalamin in complex with cyanocobalamin [PDB ID 5NP4].

Gut microbes in humans synthesize vitamin B12. Vitamin B12 functions as a modulator of the gut microbial ecology. Limitation of B12 can result from uptake disorders or dietary deficiencies. Deficiencies of the vitamin can cause anemia and permanent nerve and brain damage. Vitamin B12 is a precious resource in the gut and may not be available to the human host in significant quantities. Also, the vitamin may help to shape the structure and function of human gut microbial communities.

Johnson et al., in 2012, reported the structures of cobalamins and cobalamin riboswitches. A riboswitch is a regulatory segment of a messenger RNA that binds to small molecules. The riboswitch changes its conformation when it attaches to the target molecule - the switched RNA conformation results in a change in the production of the protein encoded by the mRNA.

Bacterial mRNAs often contain riboswitches in the 5’-untranslated regions (UTRs) of their mRNAs. The riboswitch's aptamer domain adopts a compact three-dimensional fold that acts as a scaffold for the ligand-binding pocket. Oligomers that fold into conformationally ordered structures in solution are also known as foldamers.

Cobalamin riboswitches occur widely in bacteria. The solved vitamin B12 riboswitch structures revealed insight into how the receptor and regulatory domains communicate in a ligand-dependent fashion to regulate mRNA expression.

Reference

Aptamers [ Custom Aptamer Synthesis]

Bloch JS, Ruetz M, Kräutler B, Locher KP. Structure of the human transcobalamin beta domain in four distinct states. PLoS One. 2017 Sep 14;12(9):e0184932. [
PMC]

Garst AD, Edwards AL, Batey RT. Riboswitches: structures and mechanisms. Cold Spring Harb Perspect Biol. 2011 Jun 1;3(6):a003533. [
PMC]

Foldamers [
What-is-a-Foldamer ?]

Johnson JE Jr, Reyes FE, Polaski JT, Batey RT. B12 cofactors directly stabilize an mRNA regulatory switch. Nature. 2012 Dec 6;492(7427):133-7.[
PMC]


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