Cyclic glycine-proline

Cyclic glycine-proline (cGP) is a small neuroactive peptide that belongs to a group of bioactive 2,5-diketopiperazines (2,5-DKPs) and is also known as cyclo-glycine-proline. cGP is a neutral, stable naturally occurring compound and is endogenous to the human body; found in human plasma, breast milk and cerebrospinal fluid. DKPs are bioactive compounds often found in foods. Cyclic dipeptides such as 2,5 DKPs are formed by the cyclisation of two amino acids of linear peptides produced in heated or fermented foods.[1] The bioactivity of cGP is a property of functional foods and presents in several matrices of foods including blackcurrants.[2]

Cyclic glycine-proline
Names
IUPAC name
(8aS)-2,3,6,7,8,8a-Hexahydropyrrolo[1,2-a]pyrazine-1,4-dione
Other names
Cyclo(Gly-Pro); Cyclo-Gly-Pro; Cyclo(prolylglycyl); cGP
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
DrugBank
UNII
  • InChI=1S/C7H10N2O2/c10-6-4-8-7(11)5-2-1-3-9(5)6/h5H,1-4H2,(H,8,11)/t5-/m0/s1
    Key: OWOHLURDBZHNGG-YFKPBYRVSA-N
  • C1C[C@H]2C(=O)NCC(=O)N2C1
Properties
C7H10N2O2
Molar mass 154.169 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

cGP is metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes its a more favorable candidate for manipulating the binding-release process between IGF-1 and its binding protein thereby, normalizing IGF-1 function.

IGF-1 family

Insulin growth factor-1 (IGF-1) is a hormone that is structurally very similar to insulin and mediates the effects of growth hormone (GH) thus affecting metabolism, regeneration, and overall development.[3] The GH-IGF-1 signaling pathway is crucial in the process of vascular remodeling and angiogenesis, i.e., the process of building new blood vessels and thus, helps in maintaining blood circulation in the body.[4][5] In the brain, IGF-1 is abundant in various cells and regions and research over the years, suggest an imperative role of IGF-1 activity in neurodevelopment making it critical in learning and memory.[6]

The IGF-1 family comprises

  • IGF-1,
  • IGF receptors (IGF-1R) and
  • IGF binding proteins (IGFBP).

The therapeutic applications of IGF-1 are limited due to its poor central uptake and potential side-effects. IGF-1 that is not bound to its binding protein bares a very short half-life and is cleaved by enzymes to form the tripeptide glycine-proline-glutamate (GPE). However, the enzymatic instability of GPE, with a plasma half-life of less than 4 minutes, is further cleaved to produce the final product, cyclic-Glycine-Proline (cGP).[7][8]

Biological Role of cGP

The hepatic production of IGF-1 is controlled by the growth hormone (GH)-IGF-1 axis.[9] The majority of circulating IGF-1 is not bioavailable because of its affinity and binding to IGF-binding protein (IGFBP), mainly IGFBP3. IGF-1 bioactivity is therefore, tightly regulated through reversible binding with IGFBP3.[10] It is this binding-release process that determines the amount of bioavailable IGF-1 in circulation. IGF-1 that is not bound, is cleaved into an N-terminal tripeptide, Glycine-Proline-Glutamate (GPE) and Des-N-IGF-1.[11] and GPE metabolizes to result in cyclic glycine proline (cGP)[12]

Unbound IGF-1, cleaved at the N-terminal, can be metabolized through a series of downstream enzymatic reactions to cGP. The N-terminal is the binding site of IGF-1 which allows cGP to retain the same binding affinity to IGFBP-3 and thus, regulates the bioavailability of IGF-1 through competitive binding with IGFBP3. An increase in cGP, would increase competitive advantage and thus, increase the amount of circulating and therefore, bioavailable IGF-1.[13][14][15] Research shows that cGP can normalize IGF-1 function under pathophysiological conditions of increased or diminished IGF-1 bioactivity.[16] In vitro studies show that cGP promoted the activity of IGF-1 when insufficient and inhibited the activity of IGF-1when in excess [17]

Uses

1) Cognition Vascular health is critical in maintaining cognitive function.[18] IGF-1 plays an essential role in vascular remodelling of the brain and supports cognitive retention.[19] Metabolic IGF-1 levels tend to reduce with age and this reduction appears to be a major contributor to cognitive impairment in older populations.[20][21] Low or deficient IGF-1 levels can be normalized by cGP, restoring its vascular function.[22] Studies evaluating cGP, IGF-1 and IGFBP3 levels suggest that cGP concentration and cGP/IGF-1 molar ratio were positively associated suggesting that older people with higher plasma cGP concentration (and cGP/IGF-1 molar ratio) have better memory/cognitive retention.[23]

2) Hypertension IGF-1 plays a critical role in energy metabolism with deficient IGF-1 levels being implicated in obesity and hypertension.[24]

3) Stroke The role of IGF-1 in supporting recovery from stroke, which is a condition of vascular origin, is reported.[25][26] A study in 34 stroke patients reported that patients with higher plasma concentration of cGP made better recovery within 3 months than those with lower cGP levels. Further, patients with higher cGP levels also showed lesser neurological deficits.[27]

4) Therapeutic Potential Excessive IGF-1 activity promotes tumorigenesis [28] while reduced IGF-1 activity is linked with diseases such as Alzheimer’s [29] and Parkinson’s.[30] cGP normalises the autocrine function of IGF-1 under pathological conditions and when there are low levels of cGP in the human body, IGF-1 regulation is compromised.[31] Therefore, it is reasonable to assume that treatment with exogenous cGP could assist with improving IGF-1 implicated health benefits.

References
  1. Otsuka Y, Arita H, Sakaji M, Yamamoto K, Kashiwagi T, Shimamura T, et al. Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide. Biosci Biotechnol Biochem [Internet]. 2019 Dec 2 [cited 2022 Aug 31];83(12):2355–63. Available from: https://academic.oup.com/bbb/article/83/12/2355/5937793
  2. Fan D, Alamri Y, Liu K, Macaskill M, Harris P, Brimble M, et al. Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function. Nutrients [Internet]. 2018 Jun 2 [cited 2022 Aug 31];10(6):714. Available from: /pmc/articles/PMC6024688/
  3. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Molecular Pathology [Internet]. 2001 [cited 2022 Aug 31];54(5):311. Available from: /pmc/articles/PMC1187088/
  4. Lin S, Zhang Q, Shao X, Zhang T, Xue C, Shi S, et al. IGF-1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI3K/Akt signal pathway. Cell Prolif. 2017 Dec 1;50(6).
  5. Zhang R, Kadar T, Sirimanne E, MacGibbon A, Guan J. Age-related memory decline is associated with vascular and microglial degeneration in aged rats. Behavioural brain research [Internet]. 2012 Dec 1 [cited 2022 Aug 31];235(2):210–7. Available from: https://pubmed.ncbi.nlm.nih.gov/22889927/
  6. Guan J, Harris P, Brimble M, Lei Y, Lu J, Yang Y, et al. The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders. http://dx.doi.org/101517/1472822220151010514 [Internet]. 2015 Jun 1 [cited 2022 Aug 31];19(6):785–93. Available from: https://www.tandfonline.com/doi/abs/10.1517/14728222.2015.1010514
  7. Guan J, Harris P, Brimble M, Lei Y, Lu J, Yang Y, et al. The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders. http://dx.doi.org/101517/1472822220151010514 [Internet]. 2015 Jun 1 [cited 2022 Aug 31];19(6):785–93. Available from: https://www.tandfonline.com/doi/abs/10.1517/14728222.2015.1010514
  8. Shanmugalingam T, Bosco C, Ridley AJ, van Hemelrijck M. Is there a role for IGF‐1 in the development of second primary cancers? Cancer Med [Internet]. 2016 Nov 1 [cited 2022 Aug 31];5(11):3353. Available from: /pmc/articles/PMC5119990/
  9. Bianchi VE, Locatelli V, Rizzi L. Neurotrophic and Neuroregenerative Effects of GH/IGF1. International Journal of Molecular Sciences 2017, Vol 18, Page 2441 [Internet]. 2017 Nov 17 [cited 2022 Sep 15];18(11):2441. Available from: https://www.mdpi.com/1422-0067/18/11/2441/htm
  10. Sara VR, Hall K. Insulin-like growth factors and their binding proteins. https://doi.org/101152/physrev1990703591 [Internet]. 1990 [cited 2022 Aug 11];70(3):591–614. Available from: https://journals.physiology.org/doi/10.1152/physrev.1990.70.3.591
  11. Yamamoto H, Murphy LJ. Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease. Endocrinology [Internet]. 1994 Dec 1 [cited 2022 Aug 11];135(6):2432–9. Available from: https://academic.oup.com/endo/article/135/6/2432/3036275
  12. Samonina G, Ashmarin I, Lyapina L. Glyproline peptide family: review on bioactivity and possible origins. Pathophysiology. 2002 Aug 1;8(4):229–34.
  13. Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J. Plasma cyclic glycine proline/IGF‐1 ratio predicts clinical outcome and recovery in stroke patients. Ann Clin Transl Neurol [Internet]. 2019 Apr 1 [cited 2022 Sep 5];6(4):669. Available from: /pmc/articles/PMC6469247/
  14. Fan D, Pitcher T, Dalrymple-Alford J, MacAskill M, Anderson T, Guan J. Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease. Alzheimers Dement (Amst) [Internet]. 2020 [cited 2022 Sep 5];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/32671179/
  15. Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep [Internet]. 2014 Mar 17 [cited 2022 Aug 31];4. Available from: https://pubmed.ncbi.nlm.nih.gov/24633053/
  16. Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep [Internet]. 2014 Mar 17 [cited 2022 Aug 31];4. Available from: https://pubmed.ncbi.nlm.nih.gov/24633053/
  17. Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep [Internet]. 2014 Mar 17 [cited 2022 Aug 31];4. Available from: https://pubmed.ncbi.nlm.nih.gov/24633053/
  18. Zhang R, Kadar T, Sirimanne E, MacGibbon A, Guan J. Age-related memory decline is associated with vascular and microglial degeneration in aged rats. Behavioural brain research [Internet]. 2012 Dec 1 [cited 2022 Aug 31];235(2):210–7. Available from: https://pubmed.ncbi.nlm.nih.gov/22889927/
  19. Lopez-Lopez C, LeRoith D, Torres-Aleman I. Insulin-like growth factor I is required for vessel modeling in the adult brain. Proc Natl Acad Sci U S A [Internet]. 2004 Jun 29 [cited 2022 Sep 15];101(26):9833–8. Available from: https://www.pnas.org/doi/abs/10.1073/pnas.0400337101
  20. Okereke OI, Kang JH, Ma J, Gaziano JM, Grodstein F. Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men. J Clin Endocrinol Metab [Internet]. 2006 Nov 1 [cited 2022 Sep 15];91(11):4306–12. Available from: https://academic.oup.com/jcem/article/91/11/4306/2656409
  21. Okereke O, Kang JH, Ma J, Hankinson SE, Pollak MN, Grodstein F. Plasma IGF-I levels and cognitive performance in older women. Neurobiol Aging. 2007 Jan 1;28(1):135–42.
  22. Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep [Internet]. 2014 Mar 17 [cited 2022 Aug 31];4. Available from: https://pubmed.ncbi.nlm.nih.gov/24633053/
  23. Fan D, Pitcher T, Dalrymple-Alford J, MacAskill M, Anderson T, Guan J. Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease. Alzheimers Dement (Amst) [Internet]. 2020 [cited 2022 Sep 5];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/32671179/
  24. Karmali R, Dalovisio A, Borgia JA, Venugopal P, Kim BW, Szymanski KG, et al. All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies. Blood Rev. 2015 Mar 1;29(2):71–80.
  25. Sierra C, Coca A, Schiffrin EL. Vascular Mechanisms in the Pathogenesis of Stroke. Current Hypertension Reports 2011 13:3 [Internet]. 2011 Feb 18 [cited 2022 Sep 23];13(3):200–7. Available from: https://link.springer.com/article/10.1007/s11906-011-0195-x
  26. Guan J, Bennet L, Gluckman PD, Gunn AJ. Insulin-like growth factor-1 and post-ischemic brain injury. Prog Neurobiol. 2003 Aug 1;70(6):443–62.
  27. Fan D, Krishnamurthi R, Harris P, Barber PA, Guan J. Plasma cyclic glycine proline/IGF‐1 ratio predicts clinical outcome and recovery in stroke patients. Ann Clin Transl Neurol [Internet]. 2019 Apr 1 [cited 2022 Sep 5];6(4):669. Available from: /pmc/articles/PMC6469247/
  28. Shanmugalingam T, Bosco C, Ridley AJ, van Hemelrijck M. Is there a role for IGF‐1 in the development of second primary cancers? Cancer Med [Internet]. 2016 Nov 1 [cited 2022 Aug 31];5(11):3353. Available from: /pmc/articles/PMC5119990/
  29. Kang D, Waldvogel HJ, Wang A, Fan D, Faull RLM, Curtis MA, et al. The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer’s disease. Psychoneuroendocrinology. 2021 May 1;127:105191.
  30. Fan D, Pitcher T, Dalrymple-Alford J, MacAskill M, Anderson T, Guan J. Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease. Alzheimers Dement (Amst) [Internet]. 2020 [cited 2022 Sep 5];12(1). Available from: https://pubmed.ncbi.nlm.nih.gov/32671179/
  31. Guan J, Gluckman P, Yang P, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep [Internet]. 2014 Mar 17 [cited 2022 Aug 31];4. Available from: https://pubmed.ncbi.nlm.nih.gov/24633053/
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