Insulin zinc binding

Another zinc-utilizing enzyme is carbonate/dehydratase C (Kannan et al., 1972). Here, the zinc is firmly bound by three histidyl side chains and a water molecule or a hydroxyl ion (Fig. 27). The coordination is that of a distorted tetrahedron. Metals such as Cu(II), Co(Il), and Mn(ll) bind at the same site as zinc. Hg(II) also binds near, but not precisely at, this site (Kannan et al., 1972). Horse liver alcohol dehydrogenase (Schneider et al., 1983) contains two zinc sites, one catalytic and one noncatalytic. X-Ray studies showed that the catalytic Zn(II), bound tetrahedrally to two cysteines, one histidine, and water (or hydroxyl), can be replaced by Co(II) and that the tetrahedral geometry is maintained. This is also true with Ni(Il). Insulin also binds zinc (Adams etai, 1969 Bordas etal., 1983) and forms rhombohedral 2Zn insulin crystals. The coordination of the zinc consists of three symmetry-related histidines (from BIO) and three symmetry-related water molecules. These give an octahedral complex... 

Compatibility. Soluble insulin may be mixed in the syringe with insulin zinc suspensions (amorphous, crystalline) and with isophane and mixed (biphasic) insulin, and used at once but there are insulins in which protamine is used as a carrier, and spare protamine will bind some of the short-acting neutral insulin, thus blunting its effects. 

Huus K, Havelund S, Olsen HB, et al. Ligand binding and thermostability of different allosteric states of the insulin zinc-hexamer. Biochemistry 2006 45(12) 4014-4024. 

The switch in position of amino acids in lispro does not affect the action of this synthetic insulin on cells because it is not in a critical invariant region, but it does affect the ability of insulin to bind zinc. Normally, human insulin is secreted from the pancreas as a zinc hexa-mer in which six insulin molecules are bound to the zinc atom. When zinc insulin is injected, the binding to zinc slows the absorption from the subcutaneous (under the skin) injection site. Lispro cannot bind zinc to form a hexamer, and thus it is absorbed much more quickly than other insulins. 

Birdi, K. S., 1973, The binding of cationic detergent to insulin, zinc-insulin and iso-insulin, Biochem.J. 135 253-255. 

Insulin. The chemical structure of insulin has been elucidated completely by the brilliant work of F. Sanger. The amino acid sequence is shown in Chapt. III-.3. The polypeptide consists of two chains that are cross-linked by sulfur bridges. The molecular weight is around 6,000. Insulin easily binds zinc in the process, double molecules Avith a molecular weight of 12,000, or higher aggregates, are formed (cf. Fig. 13, Chapt. IV-5). 

Answen Q Proteins with SH2 domains might bind to the insulin receptor substrate-1 (IRS-1) to transmit signals from the insulin receptor, a tyrosine kinase type of receptor. PI-3 kinase is an example of an SH2 domain protein. SH2 domains are not involved in DNA binding (choices A and D). Examples of protein domains that bind DNA include zinc fingers (steroid receptors), leudne zippers (CREB protein), and helix-turn-helbc proteins (homeodomain proteins),... 

Trace metals Zinc Red meats, shellfish, wholegrain cereals Involved in many metabolic reactions stabilisation of structure RNA, DNA and ribosomes Binding of some transcription factors to DNA Stabilisation of insulin complex in storage granules... 

The insulin monomer is of 6000 molecular weight, and either the monomer or the dimer is the active hormone. Thus in fact the zinc that binds the molecule into hexamers is not of physiological interest. What is... 

Insulin in the two zinc form binds zinc in a roughly octahedral hole. However, thiocyanate can displace the zinc to a new binding site that is created through the simultaneous anion binding in a most unusual way. Apparently, the site is a hydrophobic pocket with few dipoles anywhere in the vicinity. In fact, the hole is lined with methyl groups. 

In addition to its function in catalysis, zinc often plays an important structural role, e.g., in the zinc finger transcriptional regulators (Fig. 5-38).k Zinc ions bind to insulin and stabilize its hexameric structure (Fig. 7-18)/ Six Zn2+ ions are present in the hexagonal tail plate of the T-even bacteriophage (Box 7-C) and appear to be essential for invasion of bacteria.131 In carnivores, the tapetum, the reflecting layer behind the retina of the eye of many animals, contains crystals of the Zn2+-cysteine complex. 

Whilst growth factors in the serum provide specific proliferative stimuli, studies with cultured cells have indicated other important components for cell proliferation [18]. For example, insulin is required to facilitate glucose and amino-acid uptake, and transferrin, which binds iron, makes it available to the cell. Serum is also believed to supply trace elements such as selenium, copper and zinc as well as fatty acids important for cell growth. Some serum components such as ascorbate, a-tocopherol, caeruloplasmin and albumin may serve important antioxidant functions [19]. 

Mixing drugs formulated for injection in a syringe may cause interaction, e.g. protamine zinc insulin contains excess of protamine which binds with added soluble insulin and reduces the immediate effect of the dose. 

Zinc (Zn) Binds to enzymes throughout the body, to DNA, and to some hormones (e.g., insulin) Plays role in sexual maturation and regulation of hormones, helps some proteins stick tightly to DNA Shellfish (oysters), chick peas, baked beans, whole grains, nuts... 

Sulfatide binds directly to insulin, and sulfatide, but not its galactosyl-ceramide precursor, was able to compete with monoclonal antibodies directed against a subdomain of the insulin molecule (Osterbye et al., 2001). Sulfatide specifically promotes in vitro refolding of proinsulin into its zinc-dependent hexameric form while without a sulfatide or in the presence of galactosylcer-amide, proinsulin dimers and hexamers were nearly absent (Osterbye et al.,... 

Zinc Insulin Crystals. Crystalline preparation of the active antidiabetic principle of the internal secretion of Langerhans islands of the pancreas. The crystals contain a small amount of zinc (not less than 0.45% nor more than 0.9%), which is chemically combined with the active principle. Each milligram nf the crystals is equivalent to not less than 22 units of insulin. The product is marketed in the form of cryst zinc-insulin injection. Study of the binding of zinc by insulin Tanford, Epstein, J. Am. Chem. Soc. 76, 2170 (1954) Cunningham, et al ibid. 77, 5703 (1955). Proposed crystallographic structure Marcker, Graae, Acm Chem. Sea rid. 16, 41 (1962). 

More than 300 reactions are catalyzed by zinc-containing enzymes [82]. Zinc can be found with insulin, in the reproductive tract, in the DNA-binding proteins, and in oxidoreductases, transferases, lyases, isomerases, and ligases. 

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