Insulin Is Synthesized as a Preprohormone & Modified Within the β Cell
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p501-502
2025-11-16
41
Insulin has an AB heterodimeric structure with one intrachain (A6-A11) and two interchain disulfide bridges (A7-B7 and A20-B19) (Figure 1). The A and B chains could be synthesized in the laboratory, but attempts at a biochemical syn thesis of the mature insulin molecule yielded very poor results. The reason for this became apparent when it was discovered that insulin is synthesized as a preprohormone (molecular weight ~11,500), which is the prototype for peptides that are processed from larger precursor molecules. The hydrophobic 23-amino-acid pre-, or leader, sequence directs the molecule into the cisternae of the endoplasmic reticulum and then is removed. This results in the 9000-MW proinsulin molecule, which provides the conformation necessary for the proper and efficient formation of the disulfide bridges. As shown in Figure 1, the sequence of proinsulin, starting from the amino terminus, is B chain—connecting (C) peptide—A chain. The proinsulin molecule undergoes a series of site-specific peptide cleavages that result in the formation of equimolar amounts of mature insulin and C-peptide. These enzymatic cleavages are summarized in Figure 1.
Fig1. Structure of human proinsulin. Insulin and C-peptide molecules are connected at two sites by peptide bonds. An initial cleavage by a trypsin-like enzyme (red open arrows) followed by several cleavages by a carboxypeptidase-like enzyme (green solid arrows) results in the production of the heterodimeric (AB) insulin molecule (colored), which is held together by two intrapeptide cysteine disulfide bonds; insulin C-peptide (white).
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