Gallium-transferrin binding

Farrar G, Altmann P, Welch S, Wychrij O, Ghose B, Lejeune J, Corbett J, Prasher J Blair JA. (1990). Defective gallium-transferrin binding in Alzheimer disease and Down syndrome Possible mechanism for accumulation of aluminum in brain. Lancet 335, 747-750. 

Gallium is non-essential, but on account of the similarity between Ga3+ and Fe3+ it binds to iron transport and storage proteins such as transferrin and ferritin. The radioactive isotope of gallium, 67Ga, concentrates to a large extent in many tumours and at sites of inflammation and infection, and since many tumours overexpress the transferrin receptor it can be used for tumour imaging. 

Serum transferrin is normally only about 30% saturated with iron. This explains why it has a relatively high capacity for binding other metals and so is implicated in the transport of 67Ga,1139 which is used as an imaging agent for various soft tissue tumours and inflammatory abscesses.1140 Transferrin also facilitates movement of gallium across tumour cell membranes.1141... 

Gallium can interfere with the structural integrity of transferrin, the ircin-binding protein that transports iron in the serum. Gallium is believed to bind in the protein methionine. In microorganisms like Escherichia coli, gallium suppresses the synthesis of low-molecular weight polypeptides. It also concentrates on the surface of the cell envelope. 

E27.5 Gallium(III) can bind to transferrin and lactoferrin, and can even be incorporated into ferritin (a biological iron storage ). These enzymes use nitrogen and oxygen donors to bind iron. Since Ga(III) also has a good affinity for the same donors, it can compete with Fe(III) for the binding sites. One major difference between Fe(lll) and Ga(lII) is their redox chemistry. While Fe(Ill) can be reduced to Fe(II), Ga(Ill) cannot. This is an important... 

Lactoferrin, with a molecular weight of 8.5-9.0 x 10 and a structure similar to transferrin (112) has been suggested as an alternative intracellular gallium-binding agent (113). 

Lactoferrin binds iron with a greater affinity than transferrin (114). and is found in tissues and secretions (especially milk) which localize galllum-67 (115.116.117.118.119). It was proposed that Ga labeled to transferrin and other plasma proteins Is transferred to cellular lactoferrin due to the latter s greater chelating ability (113-120). Such a transfer of gallium-67 has been demonstrated in vitro (121), and increased concentrations of the protein has been found in tumors (122.123.124). 

The tissue distribution of gallium radionuclides is affected by many factors, such as the extent of neoplasm [62], the presence of inflammatory processes [63], sex hormone status [64], age [65], lactation [66], radiotherapy and chemotherapy treatment [67,68], amount of carrier gallium administered [69,70], and administration of compounds which block plasma protein binding of gallium [62,71]. The mechanism of uptake of Ga in tumors and abscesses has not been definitely established. One proposed mechanism suggests that Ga-transferrin interacts with specific transferrin receptors on the tumor cell, where upon binding to the cell the Ga-transferrin complex... 

McGregor SJ, Brown D, Brock JH (1991) Transferrin-gallium binding in Alzheimer s disease. Lancet 338 1394-1395... 

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