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B12 Binding Proteins Gut: First Published As 10.1136/Gut.31.1.59 on 1 January 1990

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B12 Binding Proteins Gut: First Published As 10.1136/Gut.31.1.59 on 1 January 1990 Gut, 1990, 31, 59-63 59 B12 Binding proteins Gut: first published as 10.1136/gut.31.1.59 on 1 January 1990. Downloaded from Graham Neale This article is one of a series linked with the Festschrift for Christopher Booth. See Gut Festschrift 1989; 30.) A reliable sensitive method for measuring within one to four years whereas in those taking a vitamin B12 in the circulation was first achieved vegan diet (which contains no B12) body stores at Hammersmith in 1950.' During the subse- persist for 10-15 years. Thus B12 status is in quent decade the vitamin B12 status was assessed part maintained by an effective enterohepatic of patients with a wide variety of conditions.2 circulation. This culminated in the determination ofa unique Vitamin B12 in food is bound to peptides and function for the ileum by Booth and Mollin: that other compounds. Its release from food may start of the absorption of vitamin B123. During the in the mouth but occurs primarily in the stomach course of these early studies greatly increased and duodenum. Studies in vitro suggest that a concentrations of vitamin B12 were found in low pH favours the release of vitamin B12. the serum of patients with very high leucocyte Curiously, however, in the gastrointestinal tract counts - for example, in chronic myeloid leu- B12 is not bound initially to IF. R proteins in kaemia and other myeloproliferative disorders saliva and gastric juice (vide infra) have a greater and in occasional patients with non-leukaemic affinity for the vitamin.7 R proteins transfer B12 leucocytosis.4 It was shown that circulating B12 is to IF only after their degradation by pancreatic nearly all protein bound and that raised values proteases (Figure). Failure to degrade the R were associated with an increase in the serum protein-IF complex seems to explain the malab- capacity for binding the vitamin. sorption shown in patients with pancreatic in- High values for circulating vitamin B12 were sufficiency. This defect is corrected by the also described in patients with liver cell damage administration of either pancreatic enzymes or including those with infective hepatitis, hepatic by cobinamide. Cobinamide is an analogue ofB12 tumours, congestive cardiac failure and absces- capable of displacing the vitamin from the R ses involving the liver or the subhepatic space. protein but not capable of binding to IF. It is Booth recognised the value of these observations suggested that normally unwanted and poten- http://gut.bmj.com/ in assessing the patients with pyrexias of un- tially harmful analogues ofcobalamin in ingested known cause and disturbed liver function.5 animal tissues and those produced by intestinal It had become clear by now that vitamin B12 bacteria are bound to R proteins. This prevents required specific transport proteins for absorp- their absorption from the upper gastrointestinal tion from the intestine and transport in the body tract. They are released by proteolysis in the (Figure). The proteins fall into three groups small intestine along with vitamin B12. The B12 (Tables I, II). binds specifically to IF rendering it available for on September 25, 2021 by guest. Protected copyright. absorption whereas cobalamin analogues in the gut and from bile are excreted in faeces. Never- Intrinsic factor and the intestinal passage theless the role of biliary and pancreatic secre- ofvitamin B12 tions in modulating the absorption ofvitamin B12 Intrinsic factor (IF) was first postulated in the remains poorly understood.89 Deficiencies of classical work of Castle (1930) and isolated and either bile or pancreatic enzymes are associated characterised by Grasbeck and his coworkers.6 with malabsorption ofcrystalline vitamin B12 but It is a glycoprotein of molecular weight around rarely ifever with clinical vitamin B12 deficiency. 60000, consisting of two polypeptide chains, Abnormalities of intrinsic factor (Table III) each binding one molecule ofIF. The complex is and the subsequent fate of B12-IF complex is very resistant to proteolytic digestion and quite discussed in this volume by Schjonsby.9 specific in its binding properties (much more so than the other B12 binding proteins). Intrinsic factor is essential for the absorption of B12 from Transcobalamins the gastrointestinal tract, and it is made and In plasma, B12 is bound to two main classes of secreted by gastric parietal cells in an amount proteins one with alpha-beta and the other with which greatly exceeds physiological require- ments (the mean concentration of 1,ug/ml pro- TABLE I Sources ofB,2 bindingproteins vides a binding capacity of more than 50 times requirements). The process of producing and Protein Alternative names Source secreting intrinsic factor is established early in Intrinsic Factors IF Gastric Juice Transcobalamin II TCII Liver prenatal life and in atrophic gastritis it persists Transcobalamin (Other tissues - long after the capacity to produce gastric acid has P-globulin binder probably many) R proteins R-binder Granulocytes been reduced to very low concentrations. TCI Myeloid cells A normal daily diet contains 5-15 ug vitamin TCI-III Salivary gland a Transcorrin (Other secretory cells Addenbrookes Hospital, B12 and the bile delivers further 5 ug per day Cobalophilin in the gastro- Cambridge into the duodenum. After total gastrectomy lack Leucocyte binder intestinal mucosa) Graham Neale of intrinsic factor leads to signs of B12 deficiency Salivary binder 60 Neale Salivary 'fR't Gut: first published as 10.1136/gut.31.1.59 on 1 January 1990. Downloaded from TC 11(10% Sat) TC 1l-B12 R Protein -IF (80% Sat) I I I I R-B12 analogues Figure: Role ofB,2 binding proteins in the uptake and metabolism ofvitamin B,2. http://gut.bmj.com/ beta-electrophoretic mobility. Hall and Finkler TABLE iII Disorders ofthe binding protein associated with '° provided the further characterisation which is low levels ofcirculating B,2 the basis of the classification used today. They IF deficiency Congenital IF deficiency used ion-exchange chromatography on DEAE- Post gastrectomy Pernicious anaemia cellulose and with gradient elution they separ- Abnormal IF Decreased ileal binding ated two transcobalamins TCI and TCII. TCI (Congenital disorder) on September 25, 2021 by guest. Protected copyright. Impaired transcellular Familial B12 malabsorption carries the bulk of endogenous B12 and TCII passage of B12 (Imerslund-Grasbeck) vitamin which has been recently absorbed. TCII Impaired transfer and Congenital TCII deficiency ('null' is sometimes referred to simply as transcobala- transport of B,2 allele or non-functioning TCII) min because it has a clearcut function in transfer- ring B12 to cell surface receptors and across cell tion. In this review the TCI proteins will be membranes. In contrast TCI, as originally des- called R binders (R is derived from the rapid cribed, is not a single protein. A family of electrophoretic mobility of these binding pro- proteins has emerged and the members of this teins in gastric juice compared with IF). The family are still far from being properly under- name is non-specific and so is suitable for a group stood with respect to either structure or func- of proteins which are closely related one to another but which have not been satisfactorily characterised (Table II). The function of R TABLE II Nature ofB,2 binding proteins proteins is still not clear. As indicated above they Specificity may serve as scavengers for useless and poten- Protein Nature Function of binding tially harmful cobalamin analogues and may also have an antibacterial action micro- IF MW 44 000* Promotes ileal uptake High by depriving Glycoprotein (specific receptor for organisms of vitamin B12-like substances." A dimer IF-B12) much information TC II MW 38 000* Essential for transfer, Inter- Despite these uncertainties Liver protein distribution, re- mediate has accumulated regarding the activities of TCII cycling and R proteins in the circulation even though In plasma 30 [sg/ml R proteins MW 60000* Binds endogenous B12 Low their concentrations are remarkably small (TCI/ Glycoproteins and analogues in 10 In clinical concentrations TCIII) From degrading circulation. (- ,mol/1). practice tissues In plasma 25 tg/ml are assessed indirectly by determining the equiv- From exocrine Possible antibacterial alent B12 binding capacity and expressing the glandst action results as pg vitamin B12 per ml. This is clearly *Representative weights based on amino acid and carbohydrate unsatisfactory and further progress is hampered composition and ultracentrifugation; tR proteins are found in saliva, gastric juice, bile, tears, CSF, breast milk, seminal fluid, by an inability to determine the holo- and apo- amniotic fluid as well as in plasma. proteins by direct assay. B12 Bindingproteins 61 Transcobalamin II (TCII) and the transport hypogammaglobulinaemia and possibly a killing of vitamin B12 defect of granulocytes.'7 Curiously the condition TCII is a plasma protein with P electrophorectic develops during infancy indicating that the fetus mobility which has a clearcut role in the physi- in utero has an alternative mechanism for deliver- Gut: first published as 10.1136/gut.31.1.59 on 1 January 1990. Downloaded from ology of vitamin B12. It picks up absorbed ing B12 to its tissues. Neurological defects occur vitamin B12, directs it to specific receptors on cell only if the diagnosis is long delayed (with the membranes and facilitates its transport into cells. anaemia corrected by the administration of folic Thus its role in the circulation is closely acid). Patients with TCII deficiency have low analogous to that of IF in the gut. It is probable normal values for the circulating vitamin (bound that all tissues require TCII for the adequate to R proteins) but respond to the administration uptake ofvitamin B12 and this has been shown in of large doses of Bl2. This is also true of patients several in vitro models (including reticulocytes, with apparently normal TCII binding but a lymphocytes, fibroblasts, homogenised brain failure of tissue uptake.
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