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Proinsulin Processing and Insulin Biosynthesis

1967
  • Donald F. Steiner
Researcher studying proinsulin processing in a laboratory for cell biology applications.

(generated image for illustration only)

Insulin is synthesized in pancreatic beta cells as a single-chain precursor called proinsulin. In the endoplasmic reticulum, proinsulin folds and forms its disulfide bonds. It is then transported to the Golgi apparatus and packaged into secretory granules, where proteases (prohormone convertases PC1/3 and PC2, and carboxypeptidase E) cleave it into mature insulin and a connecting peptide, C-peptide.

The discovery of proinsulin by Donald F. Steiner in 1967 resolved a key puzzle in insulin biosynthesis. It was known that insulin consisted of two separate polypeptide chains (A and B), but the mechanism for ensuring their coordinated synthesis and correct assembly via disulfide bonds was unclear. Steiner’s research revealed that a single gene codes for a larger, single-chain precursor. This preproinsulin molecule contains a signal peptide at its N-terminus that directs it into the lumen of the endoplasmic reticulum (ER). The signal peptide is quickly cleaved off, leaving proinsulin. Proinsulin consists of the B chain, a connecting C-peptide, and the A chain, in that order (B-C-A). Within the ER, the molecule folds into its proper conformation, guided by chaperones, which brings the cysteine residues into proximity, allowing the three crucial disulfide bonds to form correctly. This folded proinsulin is then transported to the Golgi complex and packaged into immature clathrin-coated secretory vesicles. As these vesicles mature into dense-core secretory granules, the internal environment becomes more acidic, activating specific endoproteases. Prohormone convertase 1/3 (PC1/3) makes the initial cut at the B-chain/C-peptide junction, and prohormone convertase 2 (PC2) cuts at the C-peptide/A-chain junction. Finally, carboxypeptidase E (CPE) trims off basic amino acid residues at the new C-termini, resulting in the final, mature two-chain insulin molecule and the free C-peptide. Both are stored in these granules and co-secreted in equimolar amounts in response to high blood glucose.

UNESCO Nomenclature: 2403
– Cell biology

Type

Biological Process

Disruption

Substantial

Usage

Widespread Use

Precursors

  • discovery of the protein synthesis pathway (ribosomes, er, golgi)
  • determination of insulin’s two-chain structure by sanger
  • development of pulse-chase labeling techniques using radioactive amino acids
  • identification of proteolytic enzymes (proteases)

Applications

  • measurement of c-peptide levels in blood to assess endogenous insulin production
  • understanding of congenital hyperproinsulinemia, a genetic disorder of proinsulin processing
  • development of single-chain insulin analogs for improved stability
  • research into protein folding and trafficking within the cell
  • providing a model system for the biosynthesis of other peptide hormones

Patents:

NA

Potential Innovations Ideas

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Related to: proinsulin, c-peptide, biosynthesis, beta cell, endoplasmic reticulum, golgi apparatus, secretory granule, protein folding, post-translational modification, donald steiner.

Historical Context

Proinsulin Processing and Insulin Biosynthesis

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(if date is unknown or not relevant, e.g. "fluid mechanics", a rounded estimation of its notable emergence is provided)

Related Invention, Innovation & Technical Principles

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