Intrinsic factor discovery

Vitamin Bn deficiency Deficiency, although rare, results in two serious problems megaloblastic anaemia (which is identical to that caused by folate deficiency) and a specific neuropathy called Bi2-associated neuropathy or cobalamin-deficiency-associated neuropathy (previously called, subacute combined degeneration of the cord). A normal healthy adult can survive more than a decade without dietary vitamin B12 without any signs of deficiency since it is synthesised by microorganisms in the colon and then absorbed. However, pernicious anaemia develops fairly rapidly in patients who have a defective vitamin B12 absorption system due to a lack of intrinsic factor. It results in death in 3 days. Minot and Murphy discovered that giving patients liver, which contains the intrinsic factor, and which is lightly cooked to avoid denaturation, cured the anaemia. For this discovery they were awarded the Nobel Prize in Medicine in 1934. 

This observation led to the discovery that a dietary compound (extrinsic factor) was absorbed only after combination with a protein secreted by the normal stomach (intrinsic factor [IF]), and that the IF was missing from the secretions of the atrophic stomach found in patients with PA. The extrinsic factor, later named vitamin B12, was obtained in crystalline form in 1948, and its structure was defined by x-ray crystallography by Dorothy Hodgkins, an accomplishment for which she received the Nobel Prize for Chemistry in 1964. 

In 1948 chemists working for Glaxo in England and for Merck in the United States isolated a crystalline compound from liver that clinical tests proved to be the extrinsic factor. Because the factor proved to be a nutritional requirement, the Americans called it vitamin B12. Isolation of vitamin B12, the discovery that it contains cobalt, and the substitution of radioactive cobalt for the stable isotope made characterization of the intrinsic factor much easier, for it was no longer necessary to find a patient in relapse and then to exhaust his usefulness in one time-consuming test of a single preparation. ... 

Determination of the cellular source of intrinsic factor followed introduction of radioactive vitamin B12 and the discovery in the late 1950s of circulating antibodies to components of the gastric mucosa. 

The discovery by Baker and Mollin (1955) of a stoichiometric relationship between intrinsic factor and B12 makes it much more probable that intrinsic factor acts on the vitamin rather than on the intestinal wall. The therapeutic implications of their work are important (page 172). 

In comparison to the level of cellular serine or threonine phosphorylation, protein tyrosine phosphorylation occurs at quite low levels in normal cells but dramatically increases upon oncogenic transformation or stimulation. Since the first discovery in 1978 that the transforming protein from Rous sarcoma virus (pp60vsrc) exhibited intrinsic kinase activity/5 protein kinase activity has also been shown to be inherent to other growth factor receptors such as epidermal growth factor receptor and the insulin receptor,[6 91 and to involve autophosphorylation processes. The diverse biochemical activity exhibited by protein tyrosine phosphorylation has stimulated the development of chemical methods for the preparation of phosphorylated peptides for use as substrates in elucidating the biochemical and physiological activity of phosphorylated site(s). 

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