Cyclic glycine-proline explained

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]

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.[3]

IGF-1 family

Insulin-like 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.[4] 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.[5] [6] 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.[7]

The IGF-1 family comprises

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).[8] [7] [9]

Biological Role of cGP

The hepatic production of IGF-1 is controlled by the growth hormone (GH)-IGF-1 axis.[10] 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.[11] 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.[12] and GPE metabolizes to result in cyclic glycine proline (cGP).[13] [14]

Unbound IGF-1, cleaved at the N-terminal, can be metabolized through a series ofdownstream 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.[15] [16] [17]

Research shows that cGP can normalize IGF-1 function under pathophysiological conditions of increased or diminished IGF-1 bioactivity.[17]

In vitro studies show that cGP promoted the activity of IGF-1 when insufficient and inhibited the activity of IGF-1 when in excess.[17]

Uses

A recently published review in the journal Marine Drugs, provides an excellent overview of cGP sources and biological effects.[18] Biologically, cGP is most strongly associated with cognitive benefits, however it also has a role in other biological functions, as outlined below.

Cognition

Vascular health is critical in maintaining cognitive function.[6] 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.[17] 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.[16]

Hypertension

IGF-1 plays a critical role in energy metabolism with deficient IGF-1 levels being implicated in obesity and hypertension.[22]

Stroke

The role of IGF-1 in supporting recovery from stroke, which is a condition of vascular origin, is reported.[23] [24] 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.[25]

Therapeutic Potential

Excessive IGF-1 activity promotes tumorigenesis[9] while reduced IGF-1 activity is linked with diseases such as Alzheimer's[26] and Parkinson's.[16] 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.[17] Therefore, it is reasonable to assume that treatment with exogenous cGP could assist with improving IGF-1 implicated health benefits.[27]

Notes and References

  1. Otsuka . Yuuki . Arita . Hikaru . Sakaji . Michio . Yamamoto . Kenji . Kashiwagi . Takehiro . Shimamura . Tomoko . Ukeda . Hiroyuki . Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide . Bioscience, Biotechnology, and Biochemistry . 2 December 2019 . 83 . 12 . 2355–2363 . 10.1080/09168451.2019.1659718 . 31462170 . 201663846 .
  2. Fan . Dawei . Alamri . Yassar . Liu . Karen . MacAskill . Michael . Harris . Paul . Brimble . Margaret . Dalrymple-Alford . John . Prickett . Tim . Menzies . Oliver . Laurenson . Andrew . Anderson . Tim . Guan . Jian . 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 . 2 June 2018 . 10 . 6 . 714 . 10.3390/nu10060714 . 29865234 . 6024688 . free .
  3. Tran . Loi Hung . US Patent # 7232798: Neuroprotection and neurogenesis by administering cyclic prolyl glycine. US Patent Trademark Office . June 19, 2007 . Priority date: Nov 13, 2001 . Filing date: Nov 12, 2002 .
  4. Laron . Z . Insulin-like growth factor 1 (IGF-1): a growth hormone . Molecular Pathology . 1 October 2001 . 54 . 5 . 311–316 . 10.1136/mp.54.5.311 . 11577173 . 1187088 .
  5. Lin . Shiyu . Zhang . Qi . Shao . Xiaoru . Zhang . Tao . Xue . Changyue . Shi . Sirong . Zhao . Dan . Lin . Yunfeng . IGF -1 promotes angiogenesis in endothelial cells/adipose-derived stem cells co-culture system with activation of PI 3K/Akt signal pathway . Cell Proliferation . December 2017 . 50 . 6 . 10.1111/cpr.12390 . 28960620 . 6529130 . 8857741 .
  6. Zhang . Rong . Kadar . Tamar . Sirimanne . Ernest . MacGibbon . Alastair . Guan . Jian . Age-related memory decline is associated with vascular and microglial degeneration in aged rats . Behavioural Brain Research . December 2012 . 235 . 2 . 210–217 . 10.1016/j.bbr.2012.08.002 . 22889927 . 22501566 .
  7. Guan . Jian . Harris . Paul . Brimble . Margaret . Lei . Yang . Lu . Jun . Yang . Yang . Gunn . Alistair J . The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders . Expert Opinion on Therapeutic Targets . 3 June 2015 . 19 . 6 . 785–793 . 10.1517/14728222.2015.1010514 . 25652713 . 19257181 .
  8. Tran . Loi Hung . US Patent # 7232798: Neuroprotection and neurogenesis by administering cyclic prolyl glycine. US Patent Trademark Office . June 19, 2007 . Priority date: Nov 13, 2001 . Filing date: Nov 12, 2002 .
  9. Shanmugalingam . Thurkaa . Bosco . Cecilia . Ridley . Anne J. . Van Hemelrijck . Mieke . Is there a role for IGF -1 in the development of second primary cancers? . Cancer Medicine . November 2016 . 5 . 11 . 3353–3367 . 10.1002/cam4.871 . 27734632 . 5119990 .
  10. Bianchi . Vittorio . Locatelli . Vittorio . Rizzi . Laura . Neurotrophic and Neuroregenerative Effects of GH/IGF1 . International Journal of Molecular Sciences . 17 November 2017 . 18 . 11 . 2441 . 10.3390/ijms18112441 . 29149058 . 5713408 . free .
  11. Sara . V. R. . Hall . K. . Insulin-like growth factors and their binding proteins . Physiological Reviews . July 1990 . 70 . 3 . 591–614 . 10.1152/physrev.1990.70.3.591 . 1694588 .
  12. Yamamoto . H . Murphy . L J . Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease. . Endocrinology . December 1994 . 135 . 6 . 2432–2439 . 10.1210/endo.135.6.7988428 . 7988428 .
  13. Tran . Loi Hung . US Patent # 7232798: Neuroprotection and neurogenesis by administering cyclic prolyl glycine. US Patent Trademark Office . June 19, 2007 . Priority date: Nov 13, 2001 . Filing date: Nov 12, 2002 .
  14. Samonina . G . Ashmarin . I . Lyapina . L . Glyproline peptide family: review on bioactivity and possible origins . Pathophysiology . August 2002 . 8 . 4 . 229–234 . 10.1016/S0928-4680(02)00018-4 . 12100966 .
  15. Fan . Dawei . Krishnamurthi . Rita . Harris . Paul . Barber . P. Alan . Guan . Jian . Plasma cyclic glycine proline/ IGF -1 ratio predicts clinical outcome and recovery in stroke patients . Annals of Clinical and Translational Neurology . April 2019 . 6 . 4 . 669–677 . 10.1002/acn3.743 . 31019991 . 6469247 . 104430959 .
  16. Fan . Dawei . Pitcher . Toni . Dalrymple-Alford . John . MacAskill . Michael . Anderson . Tim . Guan . Jian . Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease . Alzheimer's & Dementia . January 2020 . 12 . 1 . e12025 . 10.1002/dad2.12025 . 32671179 . 7346731 .
  17. Guan . Jian . Gluckman . Peter . Yang . Panzao . Krissansen . Geoff . Sun . Xueying . Zhou . Yongzhi . Wen . Jingyuan . Phillips . Gemma . Shorten . Paul R. . McMahon . Chris D. . Wake . Graeme C. . Chan . Wendy H. K. . Thomas . Mark F. . Ren . April . Moon . Steve . Liu . Dong-Xu . Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1 . Scientific Reports . 17 March 2014 . 4 . 1 . 4388 . 10.1038/srep04388 . 24633053 . 3955921 . 2014NatSR...4E4388G .
  18. Hu . Lei . Lin . Jing . Qin . Fei . Xu . Li . Luo . Lianzhong . June 2024 . Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline . Marine Drugs . en . 22 . 6 . 271 . 10.3390/md22060271 . free . 1660-3397. 11205142 .
  19. Lopez-Lopez . C. . LeRoith . D. . Torres-Aleman . I. . Insulin-like growth factor I is required for vessel remodeling in the adult brain . Proceedings of the National Academy of Sciences . 29 June 2004 . 101 . 26 . 9833–9838 . 10.1073/pnas.0400337101 . 15210967 . 470760 . 2004PNAS..101.9833L . free .
  20. Okereke . Olivia I. . Kang . Jae H. . Ma . Jing . Gaziano . J. Michael . Grodstein . Francine . Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men . The Journal of Clinical Endocrinology & Metabolism . November 2006 . 91 . 11 . 4306–4312 . 10.1210/jc.2006-1325 . 16912125 . free .
  21. Okereke . Olivia . Kang . Jae Hee . Ma . Jing . Hankinson . Susan E. . Pollak . Michael N. . Grodstein . Francine . Plasma IGF-I levels and cognitive performance in older women . Neurobiology of Aging . January 2007 . 28 . 1 . 135–142 . 10.1016/j.neurobiolaging.2005.10.012 . 16337715 . 44509810 .
  22. Karmali . Reem . Dalovisio . Andrew . Borgia . Jeffrey A. . Venugopal . Parameswaran . Kim . Brian W. . Szymanski . Kelly Grant- . Hari . Parameswaran . Lazarus . Hillard . All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies . Blood Reviews . March 2015 . 29 . 2 . 71–80 . 10.1016/j.blre.2014.09.010 . 25433571 .
  23. Sierra . Cristina . Coca . Antonio . Schiffrin . Ernesto L. . Vascular Mechanisms in the Pathogenesis of Stroke . Current Hypertension Reports . June 2011 . 13 . 3 . 200–207 . 10.1007/s11906-011-0195-x . 21331606 . 13442699 .
  24. Guan . J . Bennet . L . Gluckman . P.D . Gunn . A.J . Insulin-like growth factor-1 and post-ischemic brain injury . Progress in Neurobiology . August 2003 . 70 . 6 . 443–462 . 10.1016/j.pneurobio.2003.08.002 . 14568359 . 12719687 .
  25. Fan . Dawei . Krishnamurthi . Rita . Rita Krishnamurthi . Harris . Paul . Barber . P. Alan . Guan . Jian . April 2019 . Plasma cyclic glycine proline/ IGF -1 ratio predicts clinical outcome and recovery in stroke patients . Annals of Clinical and Translational Neurology . 6 . 4 . 669–677 . 10.1002/acn3.743 . 6469247 . 31019991 . 104430959.
  26. Kang . Dali . Waldvogel . Henry J. . Wang . Ao . Fan . Dawei . Faull . Richard L.M. . Curtis . Maurice A. . Shorten . Paul R. . Guan . Jian . The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer's disease . Psychoneuroendocrinology . May 2021 . 127 . 105191 . 10.1016/j.psyneuen.2021.105191 . 33706042 . 232116896 .
  27. Tran . Loi Hung . US Patent # 7232798: Neuroprotection and neurogenesis by administering cyclic prolyl glycine. US Patent Trademark Office . June 19, 2007 . Priority date: Nov 13, 2001 . Filing date: Nov 12, 2002 .

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