Vitamins B12 (Cobalamins) and B6 (Pyridoxine)

Now we're onto our next lot of vitamins!

Understand the complexity of B12 biosynthesis

B12 is the largest and most complex vitamin, and therefore also has a relatively complex biosynthesis pathway... or rather pathways. B12 is synthesised in microbes in either an aerobic or an anaerobic pathway. These pathways also differ in when the metal ion (Co³⁺ in the case of B12) is inserted. In the aerobic pathway, Co³⁺ is inserted at the end, but in the anaerobic pathway, Co³⁺ is inserted earlier on.

The B12 biosynthesis pathways are complex and we aren't expected to understand them fully, but the lecturer did zoom in on a couple of enzymes (probably because he studies them :P). One of these enzymes is corrin reductase (CobR), which catalyses the conversion of Co(II) to Co(I). It is also known as a flavoprotein as it uses FAD to shuttle electrons around. The other enzyme mentioned was CbiH₆₀, which helps in ring contraction (removal of one carbon from a ring, which is apparently really hard to do).

As mentioned here, B12 and heme are similar in that they both have tetrapyrrhole rings. They're not the only ones with this similar structure: many other molecules have tetrapyrrhole rings. Vitamin B12, coenzyme F430 (a Ni²⁺-containing coenzyme involved in methanogenesis), siroheme, heme and heme d₁ all have tetrapyrrhole rings and can all be derived from precorrin-2. Precorrin-2, in turn, can be derived from uroporphyrinogen III, which can be derived from 5-ALA (mentioned here).

The roles of B12 in the cell

Remember that SAM pathway that I mentioned when talking about folate? Well, B12 is also involved in that pathway. It is involved in the conversion of homocysteine and methyl-H₄ folate into methionine and H₄ folate.

Methylmalonyl-CoA mutase is another enzyme that requires B12. It converts methylmalonyl-CoA into succinyl-CoA. Without this enzyme, methylmalonyl-CoA can build up, causing methylmalonic acidemia (MMA). Symptoms of MMA include vomiting, lethargy, profound ketoacidosis, hyperammonemia, pancytopenia and even death.

Methylmalonyl-CoA mutase is not the only enzyme that requires B12. Many enzymes require a B12 coenzyme such as adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl-dependent enzymes include ribonucleotide reductase (the only enzyme that can produce deoxyribonucleotides), glutamine mutase (an enzyme that makes carbon backbones), α-methyleneglutarate mutase, isobutyryl-CoA mutase, amino mutases, dehydrases and deaminases. MeCbl-dependent enzymes include methionine synthase and methyltransferases.

B6: be aware of the different forms of B6 and some of the more important reactions which have B6 as a cofactor

B6 (pyridoxine) can come in many different forms, such as pyridoxal phosphate (PLP), pyridoxamine phosphate (PMP) and pyridoxic acid (PA). PA is excreted in urine, whereas PLP and PMP are cofactors that bind tightly to enzymes. PLP is sometimes considered a "prebiotic," or chemical present in very early life. PLP and PMP differ by one group (PLP has a carbonyl group, whereas PMP has an aminomethyl group), and can be interconverted.

B6 in amino acid biosynthesis

PMP, with its amino group, is essential in the biosynthesis of amino acids. PMP can combine with an amino acid side chain donor to form a ketimine, which can then become a quinoid intermediate and then an external aldimine. The external aldimine can then be broken down into an internal aldimine, releasing a shiny new L-amino acid in the process. The internal aldimine can then combine with glutamate to re-form PMP and α-ketoglutarate.

Know the daily requirements for B12, B6 and related disorders

B12 and B6, being vitamins, are not produced by us. Therefore, we have to get them from external sources.

B12 requirements

• Children: 1.0 μg/day
• Teenagers: 1.8-2.4 μg/day
• Adults: 2.4 μg/day
• Pregnancy: 2.6 μg/day
• Lactation: 2.8 μg/day

The main sources of B12 are meat, molluscs, fish and fortified cereals, so vegans may need supplementation.

B12 deficiency

Some of the causes of B12 deficiency are dietary insufficiency, pernicious anaemia and tapeworm infection. Pernicious anaemia is an autoimmune disease where parietal cells are destroyed. As mentioned here, parietal cells secrete intrinsic factor, which helps us to absorb B12. Therefore, without these cells, we can't get enough B12. Tapeworm infections can also affect our ability to absorb B12.

Symptoms of B12 deficiency are similar to symptoms of folate deficiency. This may be because B12 deficiency also causes a shortage of H₄ folate. B12 deficiency also causes an insufficiency of succinyl-CoA, which is needed in the TCA cycle, and a build-up of methylmalonyl-CoA (remember, methylmalonyl-CoA mutase requires B12 to work properly). A build-up of methylmalonyl-CoA may result in methylmalonic acidaemia (MMA), particularly in babies. MMA can lead to mental retardation.

B6 requirements

• Children: 0.5-0.6 mg/day
• Teenagers: 1.0-1.3 mg/day
• Adults: 1.3-1.7 mg/day (more in older adults, and more in men than in women)

B6 can be obtained from cereals, margarine, spices and yeast spreads.

B6 overdose

Too much B6 can be toxic and lead to fun symptoms like sensory neuropathy, dermatological lesions, photosensitivity and nausea.

B6 deficiency

B6 deficiency is rare, aside from in alcoholics due to their impaired absorption ability. B6 deficiency can lead to neurological issues, which may have something to do with GABA (an inhibitory neurotransmitter).