Nutritional summary

Function: Vitamin B12 (BI2) is an essential cot actor lor only three enzymes, but these have critical impact on the metabolism of amino acids, fatty acids, phospholipids, hormones and numerous other compounds.

Food sources: Rich sources include clams, crabs, liver, beef, and lamb. Pork, milk, dairy foods, and eggs contain somewhat less.

Requirements: Current intake recommendations are 2,4 (ig. d for adults, slightly more during pregnancy (2.6 p.g d) and lactation (2.8 p-g'd).

Deficiency: Low intakes may cause decreased production and abnormal constitution of blood cells (red white, thrombocytes), irreversible neurological damage with tingling and numbness of the lower limbs as well as loss of vibratory and position sense, progressive memory loss and dementia. Infertility and recurrent fetal loss recently have been attributed to B12 deficiency in some cases ( Bennett. 2001 ). Excessive intake: I here is no indication that high intake causes harm.

OH OH

OH OH

Figurr 10.34 SDt'oiiyadcnosylcobalaium

Dietary and other sources

Only bacteria arc thought to produce B12. The synthesis is more complex than that of most other small molecules in nature and involves 30 or more steps (Raux el a/.. 2000). Foods contain mainly 5-deoxyadenosyIcobalainin attd mcthyteobalamin: the latter is relatively heat resistant; photolysis can convert these forms into aquaeobal-amin or (in the presence ofCN) cyanocobalamin. A high concentration of ascorbic acid in foods can degrade 1312 in foods.

B12-rich foods are liver, meat and lish, eggs, and milk. Plant-derived foods do not contain significant amounts. Certain algae and unicellular organisms contain significant amounts of biologically active BI2 (Miyamoto el aL. 2001). Typical daily intakes of non-vegan adults in the US are between 4 and 5 |ig day i Food and Nutrition Board Institute of Medicine, 1998). People who avoid animal-derived foods are most likely to have very low B12 intake. In particular, this includes anyone who avoids clams, crab, liver, beef or lamb, or eats fewer than three sen nigs a day of pork, milk, dairy, egg. or sausage.

Digestion and absorption

Healthy people absorb about 50" •• of ingested food B12 in the distal small intestine. The absorption process is more complex than that of most other nutrients. Intestinal B12 absorption involves proteolytic release from food proteins, binding to a scries of specific carrier proteins, eventually to intrinsic factor, receptor-mediated endoeytosis, transport out of lysosomal vesicles, reassociation with another carrier protein, and transport out of the enteroeyte into circulation. A much smaller percentage of ingested BI2 ( I" n or less} can be absorbed even in the absence of intrinsic factor (Andres et at.. 2001). The mechanism responsible for such intrinsic fact or-independent uptake is not fully understood.

Digestion and endogenous B12-binders: Free BI2 binds to transcobalamins 1 and III (R-binders. haptocorrins) from saliva arid gastric secretions (Russell-Jones and Alpers. 1999). These BI2-binding proteins have an amino acid sequence similar to that of intrinsic factor, but differ in carbohydrate content. Their physiological significance remains unclear since a lack does not appear to affect B12 status noticeably, Digestion by pepsin in the acid em ironment of the stomach releases B12 from dietary proteins or endogenous B12-binding proteins. The alkaline milieu of the small intestine favors binding of B12 to intrinsic factor, which is secreted by parietal cells of the stomach together with hydrochloric acid. Normally, about 2-4 fig BI2 can be loaded onto the amount of intrinsic factor secreted per meal. Histamine H2-receptor antagonists do not significantly affect intrinsic factor secretion (Kittang et al.. 19N5), 1 low ever, suppression of acid land pepsin) output by antacids limits release of B12 from food proteins and haptocorrins and thereby impairs absorption of food B12. but not of free B12 from supplements (Force and Nahata, 1992; Carmel, 1997). The Schilling test, which uses free B12 to assess absorption, will not detect a failure to release BI2 from protein binders.

Transcobalamins I and 111 are also the main ligands of BI2 secreted with bile. Trypsin cleaves these binders and thereby releases B12,

Uptake into Ileal enterocytes; The complex of intrinsic factor and B12 binds with high affinity to a receptor on the apical surface of enterocytcs in the distal ileum. This intrinsic factor receptor (cubilin) is a giant glycoprotein <4(i0kDa) which belongs to the LDL-receptor protein family and is concentrated in coated pits of the apical membrane (Christcnscn and Birn. 20011. Binding of the intrinsic factor B12 complex to cubilin is calcium-dependent (Kozyraki et al.. 1998), Cubilin is also a high-affinity receptor for the HDL constituent apolipoprotein A-l (Kozyraki et at.. 1999). Transcellular transport: Trafficking of cubilin into lysosomes is facilitated when it is associated with an even larger member of the same giant receptor family, megalin

(I.D1 .-receptor-related protein 2, LRP2). Both cubilin and megalin bind to the receptor-associated protein (RAP), a smaller endoplasmic reticulum protein that appears to function as a chape rone, Megalin mediates the merging of its endocytotic vesicle with lysosome. Intrinsic factor is degraded by lysosomal proteases, and the I) 12 component is transported into cytosol by a specific, though as yet uncharacterized lysosomal transporter. Megalin. and possibly cubilin, is recycled to the apical membrane via dense apical tubules (Ghristensen and Birn. 2(H) I).

Most of the Bl2 taken up by the enterocyte is converted into methylcobalamine or adcnosylcobalaniin in mitochondria, as described below. Intestinal lysosomes eontain aquacobalamin as the main form (Toyoshima and (irasbeck, 1987), When and how this form is generated remains to be determined.

Eventually, Bl2 (mainly methyleobalamin) attaches to transcobalamin-11 and crosses the basolateral membrane by an unknown mechanism. Transcobalammll-mediated transport Megalin is the specific receptor for transcobalamin-II BI2 complexes. This receptor is located predominantly on the basolateral side; much smaller amounts are present at the apical side of the ileal enterocyte (BoseWu/,. 1997). This giant transporter has three distinct functions. The first function, facilitating of cubilin endoeytosis and trafficking to lysosomes. has been mentioned above. A second proposed function might be apical to basolateral transcyiosis of the B12 transcobalamin-11 complex The third function is the endocytotic uptake of

B12-lranscoba lamm- l/l 11 B)2-tood proteins peptides *

intrinsic factor 1

Intestinal lumen

B12-lranscoba lamm- l/l 11 B)2-tood proteins peptides *

intrinsic factor 1

Intestinal lumen

Brush corder membrane

Capillary lumen

Brush corder membrane

Basolateral Capillary mem bf a ne endothelium

Figure to. IS Intestinal absorption of vitamin R12

H12 truriscobaJamm-ll complexes across the basolateral membrane and steering them towards lysosomes. This pathway provides B12 lor the enteroeyte s own uses.

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