EARLY STAGES IN THE METABOLISM OF IRON 



By J. B. Neilands 



Department of Biochemistry, University of California, 

 Berkeley, California 



There are certain chemical and biochemical characteristics of iron which place 

 it in a unique category in relation to the other common biocatalytic elements. 

 Both ferric and ferrous ions are quite insoluble in aqueous solution at physio- 

 logical pH; this property is of special significance in the case of ferric ion 

 (solubility product 10^^^) since most of the iron available to living organisms 

 will be encountered, at least initially, in the higher oxidation state. If one 

 considers the very large proportion of iron that takes part in the transport 

 and storage of oxygen as catalytic iron, then the latter element is seen to be 

 quantitatively the single most important biocatalytic element in the entire 

 realm of animal enzymology. Finally, since iron is bound relatively weakly 

 to the usual type of naturally-occurring ligand, it might be expected that living 

 cells, especially those with a high requirement for this metal, would have 

 found it necessary to evolve special complexing agents which have the 

 capacity to overcome such problems that are inherent in the transport and 

 metabolism of this particular element. 



The complete synthesis of an iron-enzyme involves the ultimate conver- 

 gence of at least two, possibly three, biosynthetic pathways. If the broad 

 definition of an iron-enzyme given above is adopted, it is clear that in many 

 instances the major portion of enzyme iron will occur as the porphyrin chelate, 

 i.e. haem. The early stages in the biosyntheis of the organic part of this pros- 

 thetic group have been thoroughly elucidated at least to the level of porpho- 

 bilinogen (Shemin, 1955; Laver, Neuberger and Udenfriend, 1958) and 

 partially clarified from thence to coproporphyrinogen (Granick and 

 Mauzerall, 1958). Little exact information is available as yet concerning the 

 immediate precursor of protoporphyrin although from the vitamin require- 

 ments for haem synthesis (Lascelles, 1957) it might be speculated that an 

 acrylic acid side chain should occur as an intermediate between the carboxy- 

 ethyl and vinyl side chains. 



In recent years many investigators have examined the mechanism of uptake 

 of iron by protoporphyrin. The concensus of opinion appears to be that the 

 reaction is enzyme-catalyzed although the specific protein responsible for the 

 observed effect has not been isolated. Until the latter has been achieved, the 

 precise nature of the iron donor in the reaction will remain obscure. 



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