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Following endocytosis, the HoloTC complex is degraded in lysosomes and free B12 is released into the cytoplasm, via CblF (Rutsch et al., 2009) and CblJ ( This free cytoplasmic B12 undergoes a series of intracellular transport and modifications to enable two core enzymatic reactions: 1) adenosyl-B12 acts as a co-factor for the enzyme methylmalonyl-coA mutase that catalyzes the conversion of methylmalonyl-coA to succinyl-coA, thereby enabling restoration of tricarboxylic acid (TCA) cycle intermediates and 2) methyl-B12 enables methionine synthase in the re-methylation of homocysteine to methionine using methyl-tetrahydrofolate (MTHF) as a methyl donor, thereby enabling the vital biochemical pathways of the folate cycle and methionine cycle, facilitating the downstream synthesis of important compounds like DNA and RNA (Figure 2)

However, few PCPs are aware of or use FIB-4

Specifically, a total of 11 sites have been proven to generate ROS in the ETC, a finding which has been reviewed elsewhere (47, 48)

Banaclocha, M