Insulin molecular derivatives

TABLE 13.13. Molecular derivatives of insulin and their pharmacologic attributes... 

Clark and Corrigan were able to determine direct identity periods of 74.7 A and 30.6 A in crystalline insulin and derived a molecular weight of about 39000. Similar results were obtained by Wyckoff and Corey on haemoglobin. The same authors were able to measure periods of 100 and 330 A directly in proteins, especially in the tail sinew of the kangaroo and in quills and porcupine bristles finally, Clark, Parker, Schaad and Warren measured network plane distances of about 440 A in collagen. 

Furthermore, the neo-Darwinian hypothesis says that the insulin gene had been duplicated long ago and that the left-over copy has mutated into a relaxin.6 Once the astronomical number of mutations had led to an active relaxin any further mutation that would hit the invariant positions would have killed or severely handicapped the owner of that hormone, and therefore all constant residues are important. My colleague Dr. Erika Biillesbach has developed an ingenious as well as practical way to synthesize relaxin and insulin for our NIH-funded research.3 These derivatives allowed us to experimentally test some of the postulated mechanisms in the Darwinian model of molecular evolution. 

The insulin receptor is present in trace amounts in the plasma membrane of liver cells. Using radiolabeled arylazido derivatives of insulin, which on irradiation yield reactive nitrenes, components of the receptor with molecular weights of 135,000 and 90,000 daltons have been identified (Jacobs etal., 1979 Yip etal., 1980 Wisher etal., 1980). The identity of the two polypeptides has been confirmed by chemical crosslinking to radiolabeled insulin and by purification of the receptor by affinity chromatography. 

Initially, we evaluated the pharmacological activities of insulin and its acyl derivatives by measuring plasma glucose levels after their intravenous injection [58]. As shown in Fig. 5.7, mono- or dicaproyl insulin (Cap-1, Cap-2) and monolauroyl insulin (Lau-1) still possessed relatively high pharmacological activities, although the potencies of the new derivatives was reduced as their molecular weight increased. 

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