Ferritin-Fe(III) was rapidly and quantitatively reduced and liberated as Fe(II) by FMNH(2), FADH(2) and reduced riboflavin. Dithionite also released Fe(II) from ferritin but at less than 1% of the rate with FMNH(2). Cysteine, glutathione and ascorbate gave a similar slower rate and yielded less than 20% of the total iron from ferritin within a few hours. The reduction of ferritin-Fe(III) by the three riboflavin compounds gave complex second-order kinetics with overlapping fast and slow reactions. The fast reaction appeared to be non-specific and may be due to a reduction of Fe(III) of a lower degree of polymerization, equilibrated with ferritin iron. The amount of this Fe(3+) ion initially reduced was small, less than 0.3% of the total iron. Addition of FMN to the ferritin-dithionite system enhanced the reduction; this is due to the reduction of FMN by dithionite to form FMNH(2) which then reduces ferritin-Fe(III). A comparison of the thermodynamic parameters of FMNH(2)-ferritin and dithionite-ferritin complex formation showed that FMNH(2) required a lower activation energy and a negative entropy change, whereas dithionite required 50% more activation energy and showed a positive entropy change in ferritin reduction. The effectiveness of FMNH(2) in ferritin-Fe(III) reduction may be due to a specific binding of the riboflavin moiety to the protein portion of the ferritin molecule.

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The non-covalent interactions of biological molecules provide the flexibility and specificity required in most important biological processes relating to the regulation of metabolism. They provide a sharp contrast with covalent biochemical compounds which supply the structural firmness and the energy reservoir for living systems.Why do antibodies react so specifically and so strongly with their respective antigens? What is the basis for deoxyribonucleic acid (DNA) being found most frequently in pairs, tightly associated in a double stranded helix. Why do hormones attach reversibly to target cell membranes and not to the membranes of other cells? How is iron transported and fed principally to those cells which need it for hemoglobin biosynthesis? Why does the hemoglobin molecule consist of an aggregate of four polypeptide chains? How can the substitution of one out of 300 amino acids in the hemoglobin mutation of sickle cell anemia distort the shape of the molecule so that the entire cell is forced to assume an abnormal form?The concept which unifies the explanation for these and a host of other important biological phenomena may be described as intermolecular interactions of the non-covalent type or simply "non-covalent interactions." This distinguishes these interactions from the more common combination of atoms and/or molecules by covalent bond formation. The typical molecule is an assembly of atoms which is held together very tightly by one or more covalent bonds. Covalent bonds identify the typical highly stable intramolecular linkage formed by two atoms which share electrons. Biological systems are dependent on covalent compounds as sources of energy for the myriad of energy requiring processes and for most of the structural elements of all organisms at many different levels.But for the conduct of their business, for the regulation of the rates and direction of biological reactions, living systems need more flexibility. This flexibility is provided by the utilization of a large number of non-covalent interactions to bring two or more molecules together to realize a specific biological objective. The formation of a non-covalent complex between molecules A and B rather than a covalent bonded compound, A-B, provides a rapid and reversible way to associate two molecules with properties and functions of which neither molecule alone is capable. It permits the reutilization of vital molecules such as enzymes, hormones, and vitamins, which may be difficult to synthesize or to obtain from the environment. At the same time, non-covalent interactions do not sacrifice the options for specificity which are so necessary for unique biochemical reactions. Thus adaptability, selectivity, reversibility and economy are promoted by these subtle chemical linkages between molecules of all sizes found in living systems.

The remarkable development of molecular biology has had its counterpart in an impressive growth of a segment of biology that might be described as atomic biology (1). The past several decades have witnessed an explosive increase in our knowledge of the many elements that are essential for life and maintenance of plants and animals. This research also encompasses the subject area which is frequently identified as bio-inorganic chemistry and trace element research. Summarized in Table 1 are the 30 essential elements classified into the six bulk or structural elements, five macrominerals, and 19 trace elements. The dominance of the eleven common

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Human ceruloplasmin (ferroxidase, EC 1.12.3.1) contains multiple binding sites for divalent transition metal ions. Equilibrium dialysis studies revealed that besides the 7 Cu ions found in the native protein, ceruloplasmin can bind an additional 10 Cu(II)'s which can be removed by Chelex. In independent and separate experiments, 3 Zn(II), 7 Ni(II), and 16 Co(II) were also bound to native ceruloplas-