Proinsulin

Last updated
insulin
Insulin path.svg
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.
Identifiers
SymbolINS
NCBI gene 3630
HGNC 6081
OMIM 176730
RefSeq NM_000207
UniProt P01308
Other data
Locus Chr. 11 p15.5
Search for
Structures Swiss-model
Domains InterPro

Proinsulin is the prohormone precursor to insulin made in the beta cells of the Pancreatic Islets, specialized regions of the pancreas. In humans, proinsulin is encoded by the INS gene. [1] [2] The pancreatic islets only secrete between 1% and 3% of proinsulin intact. [3] However, because proinsulin has a longer half life than insulin, it can account for anywhere from 5–30% of the insulin-like structures circulating in the blood. [3] There are higher concentrations of proinsulin after meals and lower levels when a person is fasting. [3] Additionally, while proinsulin and insulin have structural differences, proinsulin does demonstrate some affinity for the insulin receptor. Due to the relative similarities in structure, proinsulin can produce between 5% and 10% of the metabolic activity similarly induced by insulin. [3]

Contents

Proinsulin is the final single chain protein structure secreted by cells before cleavage into mature insulin. [4] Proinsulin was discovered by Professor Donald F. Steiner of the University of Chicago in 1967. [5]

Structure

Proinsulin is made up of 86 residues in humans (81 in cows), [6] and formed by three distinct chains. [7] The A chain, B chain, and the area connecting the two named the C peptide. [7] The correct structure of proinsulin is crucial for the correct folding of mature insulin, as the placement of the C peptide sets the molecule up to create correctly positioned disulfide bonds in and between the A and B chains. [7] [8] There are three disulfide bonds that are necessary for mature insulin to be the correct structure. Two of these disulfide bonds are between the A and B chains, and one is an intra-A chain bond. [7] The disulfide bonds occur between the seventh residues of the A and B chain, the 20th residue of the A chain and the 19th residue of the B chain, and the 6th and 11th residues of the A chain. [9]

The C peptide is between the A and B chains of proinsulin. [7] The connection between the A chain and C peptide is much more stable than the junction between the C peptide and B chain, with alpha helical features being exhibited near the C peptide-A chain connection. [10] The C peptide-A chain junction occurs between residues 64 and 65 of proinsulin. These are lysine and arginine molecules, respectively. [10] The C peptide-B chain connection is between two arginine residues at positions 31 and 32 of proinsulin. [10]

There is conservation of much of the structure of proinsulin among mammalian species, with much of the residue changes seen from one species to another present in the C peptide. [8] [11] That said, the residues of the C peptide that are conserved across species interact with similarly conserved residues on the A and B chains. [8] Thus, it is hypothesized that these conserved residues are important for the functionality of mature insulin. [8]

Synthesis and Post-translational Modification

Proinsulin is synthesized on membrane associated ribosomes found on the rough endoplasmic reticulum, where it is folded and its disulfide bonds are oxidized. It is then transported to the Golgi apparatus where it is packaged into secretory vesicles, and where it is processed by a series of proteases to form mature insulin. Mature insulin has 35 fewer amino acids; 4 are removed altogether, and the remaining 31 form the C-peptide. The C-peptide is abstracted from the center of the proinsulin sequence; the two other ends (the B chain and A chain) remain connected by disulfide bonds.[ citation needed ]

The post translational modification of proinsulin to mature insulin only occurs in the beta cells of the pancreatic islets. [12] When proinsulin is transported through the Golgi apparatus the C-peptide is cleaved. [9] This cleavage occurs with the aid of two endoproteases. [13] Type I endoproteases, PC1 and PC3, disrupt the C peptide-B chain connection. [13] PC2, a type II endoprotease, cleaves the C peptide-A chain bond. [13] The resulting molecule, now mature insulin, is stored as a hexamer in secretory vesicles and is stabilized with ions until it is secreted. [9]

Immunogenicity

When insulin was originally purified from bovine or porcine pancreata, all the proinsulin was not fully removed. [14] [15] When some people used these insulins, the proinsulin may have caused the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin was injected. This can be described as an iatrogenic injury due to slight differences between the proinsulin of different species. Since the late 1970s, when highly purified porcine insulin was introduced, and the level of insulin purity reached 99%, this ceased to be a significant clinical issue. [16] With respect to their influence on insulin pharmacokinetics, moderate concentrations of certain insulin antibodies may be of positive advantage to all diabetics without endogenous insulin secretion (e.g. people with type 1 diabetes) because insulin binding antibodies effectively increase the insulin's clearance rate and distribution space and help to prolong its pharmacological and biological half lives. [17] [ clarification needed ]

Medical Relevance

Historically, the focus of many insulin related metabolic diseases has focused on mature insulin. However, in recent years the importance of studying the structure and function of proinsulin or proinsulin:insulin ratio [18] in relation to these diseases has become increasingly clear.

Diabetes Mellitus

Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes. [19] Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding. [9] If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein. [9] This stress, after a while, would lead to a decrease in the number of β-cells producing mature insulin, and would then lead to diabetes mellitus. [9]

Neonatal Diabetes Mellitus

Postnatal proinsulin is crucial for metabolic regulation. However, proinsulin in neonates is important for normal development of the nerves of the eye, development of the heart, and general survival of embryonic cells. [20] Regulation of the concentration of proinsulin during embryonic development is crucial, as too much or too little of the peptide can cause defects and death of the fetus. [20] Thus far in the study of neonatal diabetes mellitus, only amino acid change mutations found in the B domain lead to the disease. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin</span> Peptide hormone

Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells), are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Post-translational modification</span> Biological processes

Post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes translating mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Peptide hormone</span> Hormone whose molecules are peptides

Peptide hormones are hormones whose molecules are peptides. Peptide hormones have shorter amino acid chain lengths than protein hormones. These hormones have an effect on the endocrine system of animals, including humans. Most hormones can be classified as either amino acid–based hormones or steroid hormones. The former are water-soluble and act on the surface of target cells via second messengers; the latter, being lipid-soluble, move through the plasma membranes of target cells to act within their nuclei.

<span class="mw-page-title-main">C-peptide</span> Chemical compound

The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In the context of diabetes or hypoglycemia, a measurement of C-peptide blood serum levels can be used to distinguish between different conditions with similar clinical features.

<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in the spermatozoon than histones, but they must be decompressed before the genetic data can be used for protein synthesis. However, part of the sperm's genome is packaged by histones thought to bind genes that are essential for early embryonic development.

<span class="mw-page-title-main">Proprotein convertase 1</span>

Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an enzyme that in humans is encoded by the PCSK1 gene. PCSK1 and PCSK2 differentially cleave proopiomelanocortin and they act together to process proinsulin and proglucagon in pancreatic islets.

<span class="mw-page-title-main">Vitronectin</span> Protein

Vitronectin is a glycoprotein of the hemopexin family which is synthesized and excreted by the liver, and abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the VTN gene.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal peptide hormone Involved in glucose homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Carboxypeptidase</span>

A carboxypeptidase is a protease enzyme that hydrolyzes (cleaves) a peptide bond at the carboxy-terminal (C-terminal) end of a protein or peptide. This is in contrast to an aminopeptidases, which cleave peptide bonds at the N-terminus of proteins. Humans, animals, bacteria and plants contain several types of carboxypeptidases that have diverse functions ranging from catabolism to protein maturation. At least two mechanisms have been discussed.

Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is furin. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.

<span class="mw-page-title-main">Proprotein convertase 2</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such as the conversion of proinsulin to insulin intermediates. To generate the bioactive form of insulin, a second step involving the removal of C-terminal basic residues is required; this step is mediated by carboxypeptidases E and/or D. PC2 plays only a minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis compared to PC1. PC2 binds to the neuroendocrine protein named 7B2, and if this protein is not present, proPC2 cannot become enzymatically active. 7B2 accomplishes this by preventing the aggregation of proPC2 to inactivatable forms. The C-terminal domain of 7B2 also inhibits PC2 activity until it is cleaved into smaller inactive forms that lack carboxy-terminal basic residues. Thus, 7B2 is both an activator and an inhibitor of PC2. PC2 has been identified in a number of animals, including C. elegans.

<span class="mw-page-title-main">Carboxypeptidase E</span> Protein-coding gene in the species Homo sapiens

Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.

<span class="mw-page-title-main">Insulin/IGF/Relaxin family</span> Group of proteins

The insulin/IGF/relaxin family is a group of evolutionary related proteins which possess a variety of hormonal activities. Family members in human include two subfamilies:

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Carboxypeptidase D can refer to one of several enzymes. A family of serine carboxypeptidases includes is an enzyme. This enzyme has an optimal pH of 4.5-6.0, is inhibited by diisopropyl fluorophosphate, and catalyses the following chemical reaction

A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding additional peptide chains to certain ends, that makes hormone receptor binding sites located on its peptide hormone chain segments inaccessible. Prohormones can travel the blood stream as a hormone in an inactivated form, ready to be activated later in the cell by post-translational modification.

References

  1. ↑ "Entrez Gene: INS insulin".
  2. ↑ Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". Nature. 284 (5751): 26–32. Bibcode:1980Natur.284...26B. doi:10.1038/284026a0. PMID   6243748. S2CID   4363706.
  3. 1 2 3 4 "Interpretation for 80908 Proinsulin, Plasma". www.mayomedicallaboratories.com. Archived from the original on 2017-10-04. Retrieved 2017-03-09.
  4. ↑ Assali NS, Clark KE, Zugaib M, Brinkman CR, Nuwayhid B (1995). "Effects of estrogenic hormones on uteroplacental hemodynamics and progesterone production in the sheep". International Journal of Fertility. 23 (3): 219–23. PMC   8333766 . PMID   40897.
  5. ↑ Philipson LH, Bell G, Polonsky KS (January 2015). "Donald F. Steiner MD, 1930-2014: discoverer of proinsulin". Proceedings of the National Academy of Sciences of the United States of America. 112 (4): 940–1. Bibcode:2015PNAS..112..940P. doi: 10.1073/pnas.1423774112 . PMC   4313841 . PMID   25561547.
  6. ↑ Universal protein resource accession number P01308 for " INS_HUMAN" at UniProt.
  7. 1 2 3 4 5 Nolan C, Margoliash E, Peterson JD, Steiner DF (May 1971). "The structure of bovine proinsulin". The Journal of Biological Chemistry. 246 (9): 2780–95. doi: 10.1016/S0021-9258(18)62252-5 . PMID   4928892.
  8. 1 2 3 4 Snell CR, Smyth DG (August 1975). "Proinsulin: a proposed three-dimensional structure". The Journal of Biological Chemistry. 250 (16): 6291–5. doi: 10.1016/S0021-9258(19)41065-X . PMID   808541.
  9. 1 2 3 4 5 6 7 Weiss MA (July 2009). "Proinsulin and the genetics of diabetes mellitus". The Journal of Biological Chemistry. 284 (29): 19159–63. doi: 10.1074/jbc.R109.009936 . PMC   2740536 . PMID   19395706.
  10. 1 2 3 Yang Y, Hua QX, Liu J, Shimizu EH, Choquette MH, Mackin RB, Weiss MA (March 2010). "Solution structure of proinsulin: connecting domain flexibility and prohormone processing". The Journal of Biological Chemistry. 285 (11): 7847–51. doi: 10.1074/jbc.c109.084921 . PMC   2832934 . PMID   20106974.
  11. ↑ Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". Nature. 284 (5751): 26–32. Bibcode:1980Natur.284...26B. doi:10.1038/284026a0. PMID   6243748. S2CID   4363706.
  12. ↑ Groskreutz DJ, Sliwkowski MX, Gorman CM (February 1994). "Genetically engineered proinsulin constitutively processed and secreted as mature, active insulin" (PDF). The Journal of Biological Chemistry. 269 (8): 6241–5. doi: 10.1016/S0021-9258(17)37593-2 . PMID   8119968.
  13. 1 2 3 Kaufmann JE, Irminger JC, Halban PA (September 1995). "Sequence requirements for proinsulin processing at the B-chain/C-peptide junction". The Biochemical Journal. 310 (3): 869–74. doi:10.1042/bj3100869. PMC   1135976 . PMID   7575420.
  14. ↑ Wilson RM, Douglas CA, Tattersall RB, Reeves WG (September 1985). "Immunogenicity of highly purified bovine insulin: a comparison with conventional bovine and highly purified human insulins". Diabetologia. 28 (9): 667–70. doi: 10.1007/BF00291973 . PMID   3905477.
  15. ↑ Tanyolac S, Goldfine ID, Kroon L. "Insulin Pharmacology, Type of Regimens and Adjustments". Endotext.com. Archived from the original on 2011-07-25. Retrieved 2011-03-18.
  16. ↑ Home PD, Alberti KG (November 1982). "The new insulins. Their characteristics and clinical indications". Drugs. 24 (5): 401–13. doi:10.2165/00003495-198224050-00003. PMID   6756879. S2CID   28616749.
  17. ↑ Gray RS, Cowan P, di Mario U, Elton RA, Clarke BF, Duncan LJ (June 1985). "Influence of insulin antibodies on pharmacokinetics and bioavailability of recombinant human and highly purified beef insulins in insulin dependent diabetics". British Medical Journal. 290 (6483): 1687–91. doi:10.1136/bmj.290.6483.1687. PMC   1416075 . PMID   3924216.
  18. ↑ Mezza T, Ferraro PM, Sun VA, Moffa S, Cefalo CM, Quero G, et al. (November 2018). "Increased β-Cell Workload Modulates Proinsulin-to-Insulin Ratio in Humans". Diabetes. 67 (11): 2389–2396. doi:10.2337/db18-0279. hdl: 2434/587996 . PMID   30131390. S2CID   52058695.
  19. ↑ Mykkänen L, Haffner SM, Hales CN, Rönnemaa T, Laakso M (December 1997). "The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects". Diabetes. 46 (12): 1990–5. doi:10.2337/diab.46.12.1990. PMID   9392485. S2CID   44874023.
  20. 1 2 Hernández-Sánchez C, Mansilla A, de la Rosa EJ, de Pablo F (June 2006). "Proinsulin in development: New roles for an ancient prohormone". Diabetologia. 49 (6): 1142–50. doi: 10.1007/s00125-006-0232-5 . hdl: 10261/72608 . PMID   16596360.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.