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).[6][7]

Biological Role of cGP

The hepatic production of IGF-1 is controlled by the growth hormone (GH)-IGF-1 axis.[8] 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.[9] 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.[10] and GPE metabolizes to result in cyclic glycine proline (cGP).[11]

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.[12][13][14]

Research shows that cGP can normalize IGF-1 function under pathophysiological conditions of increased or diminished IGF-1 bioactivity.[14]

In vitro studies show that cGP promoted the activity of IGF-1 when insufficient and inhibited the activity of IGF-1 when in excess.[14]

Uses

Cognition

Vascular health is critical in maintaining cognitive function.[15] IGF-1 plays an essential role in vascular remodelling of the brain and supports cognitive retention.[16] Metabolic IGF-1 levels tend to reduce with age and this reduction appears to be a major contributor to cognitive impairment in older populations.[17][18]

Low or deficient IGF-1 levels can be normalized by cGP, restoring its vascular function.[14] 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.[13]

Hypertension

IGF-1 plays a critical role in energy metabolism with deficient IGF-1 levels being implicated in obesity and hypertension.[19]

Stroke

The role of IGF-1 in supporting recovery from stroke, which is a condition of vascular origin, is reported.[20][21] 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.[22]

Therapeutic Potential

Excessive IGF-1 activity promotes tumorigenesis[7] while reduced IGF-1 activity is linked with diseases such as Alzheimer’s[23] and Parkinson’s.[13] 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.[14] Therefore, it is reasonable to assume that treatment with exogenous cGP could assist with improving IGF-1 implicated health benefits.

References
  1. Otsuka, Yuuki; Arita, Hikaru; Sakaji, Michio; Yamamoto, Kenji; Kashiwagi, Takehiro; Shimamura, Tomoko; Ukeda, Hiroyuki (2 December 2019). "Investigation of the formation mechanism of proline-containing cyclic dipeptide from the linear peptide". Bioscience, Biotechnology, and Biochemistry. 83 (12): 2355–2363. doi:10.1080/09168451.2019.1659718. PMID 31462170. S2CID 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 (2 June 2018). "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. 10 (6): 714. doi:10.3390/nu10060714. PMC 6024688. PMID 29865234.
  3. Laron, Z (1 October 2001). "Insulin-like growth factor 1 (IGF-1): a growth hormone". Molecular Pathology. 54 (5): 311–316. doi:10.1136/mp.54.5.311. PMC 1187088. PMID 11577173.
  4. Lin, Shiyu; Zhang, Qi; Shao, Xiaoru; Zhang, Tao; Xue, Changyue; Shi, Sirong; Zhao, Dan; Lin, Yunfeng (December 2017). "IGF ‐1 promotes angiogenesis in endothelial cells/adipose‐derived stem cells co‐culture system with activation of PI 3K/Akt signal pathway". Cell Proliferation. 50 (6). doi:10.1111/cpr.12390. PMC 6529130. PMID 28960620. S2CID 8857741.
  5. Zhang, Rong; Kadar, Tamar; Sirimanne, Ernest; MacGibbon, Alastair; Guan, Jian (December 2012). "Age-related memory decline is associated with vascular and microglial degeneration in aged rats". Behavioural Brain Research. 235 (2): 210–217. doi:10.1016/j.bbr.2012.08.002. PMID 22889927. S2CID 22501566.
  6. Guan, Jian; Harris, Paul; Brimble, Margaret; Lei, Yang; Lu, Jun; Yang, Yang; Gunn, Alistair J (3 June 2015). "The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders". Expert Opinion on Therapeutic Targets. 19 (6): 785–793. doi:10.1517/14728222.2015.1010514. PMID 25652713. S2CID 19257181.
  7. Shanmugalingam, Thurkaa; Bosco, Cecilia; Ridley, Anne J.; Van Hemelrijck, Mieke (November 2016). "Is there a role for IGF ‐1 in the development of second primary cancers?". Cancer Medicine. 5 (11): 3353–3367. doi:10.1002/cam4.871. PMC 5119990. PMID 27734632.
  8. Bianchi, Vittorio; Locatelli, Vittorio; Rizzi, Laura (17 November 2017). "Neurotrophic and Neuroregenerative Effects of GH/IGF1". International Journal of Molecular Sciences. 18 (11): 2441. doi:10.3390/ijms18112441. PMC 5713408. PMID 29149058.
  9. Sara, V. R.; Hall, K. (July 1990). "Insulin-like growth factors and their binding proteins". Physiological Reviews. 70 (3): 591–614. doi:10.1152/physrev.1990.70.3.591. PMID 1694588.
  10. Yamamoto, H; Murphy, L J (December 1994). "Generation of des-(1-3) insulin-like growth factor-I in serum by an acid protease". Endocrinology. 135 (6): 2432–2439. doi:10.1210/endo.135.6.7988428. PMID 7988428.
  11. Samonina, G; Ashmarin, I; Lyapina, L (August 2002). "Glyproline peptide family: review on bioactivity and possible origins". Pathophysiology. 8 (4): 229–234. doi:10.1016/S0928-4680(02)00018-4. PMID 12100966.
  12. Fan, Dawei; Krishnamurthi, Rita; 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. doi:10.1002/acn3.743. PMC 6469247. PMID 31019991. S2CID 104430959.
  13. Fan, Dawei; Pitcher, Toni; Dalrymple‐Alford, John; MacAskill, Michael; Anderson, Tim; Guan, Jian (January 2020). "Changes of plasma cGP/IGF‐1 molar ratio with age is associated with cognitive status of Parkinson disease". Alzheimer's & Dementia. 12 (1): e12025. doi:10.1002/dad2.12025. PMC 7346731. PMID 32671179.
  14. 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 (17 March 2014). "Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1". Scientific Reports. 4 (1): 4388. Bibcode:2014NatSR...4E4388G. doi:10.1038/srep04388. PMC 3955921. PMID 24633053.
  15. Zhang, Rong; Kadar, Tamar; Sirimanne, Ernest; MacGibbon, Alastair; Guan, Jian (December 2012). "Age-related memory decline is associated with vascular and microglial degeneration in aged rats". Behavioural Brain Research. 235 (2): 210–217. doi:10.1016/j.bbr.2012.08.002. PMID 22889927. S2CID 22501566.
  16. Lopez-Lopez, C.; LeRoith, D.; Torres-Aleman, I. (29 June 2004). "Insulin-like growth factor I is required for vessel remodeling in the adult brain". Proceedings of the National Academy of Sciences. 101 (26): 9833–9838. Bibcode:2004PNAS..101.9833L. doi:10.1073/pnas.0400337101. PMC 470760. PMID 15210967.
  17. Okereke, Olivia I.; Kang, Jae H.; Ma, Jing; Gaziano, J. Michael; Grodstein, Francine (November 2006). "Midlife Plasma Insulin-Like Growth Factor I and Cognitive Function in Older Men". The Journal of Clinical Endocrinology & Metabolism. 91 (11): 4306–4312. doi:10.1210/jc.2006-1325. PMID 16912125.
  18. Okereke, Olivia; Kang, Jae Hee; Ma, Jing; Hankinson, Susan E.; Pollak, Michael N.; Grodstein, Francine (January 2007). "Plasma IGF-I levels and cognitive performance in older women". Neurobiology of Aging. 28 (1): 135–142. doi:10.1016/j.neurobiolaging.2005.10.012. PMID 16337715. S2CID 44509810.
  19. Karmali, Reem; Dalovisio, Andrew; Borgia, Jeffrey A.; Venugopal, Parameswaran; Kim, Brian W.; Szymanski, Kelly Grant‐; Hari, Parameswaran; Lazarus, Hillard (March 2015). "All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies". Blood Reviews. 29 (2): 71–80. doi:10.1016/j.blre.2014.09.010. PMID 25433571.
  20. Sierra, Cristina; Coca, Antonio; Schiffrin, Ernesto L. (June 2011). "Vascular Mechanisms in the Pathogenesis of Stroke". Current Hypertension Reports. 13 (3): 200–207. doi:10.1007/s11906-011-0195-x. PMID 21331606. S2CID 13442699.
  21. Guan, J; Bennet, L; Gluckman, P.D; Gunn, A.J (August 2003). "Insulin-like growth factor-1 and post-ischemic brain injury". Progress in Neurobiology. 70 (6): 443–462. doi:10.1016/j.pneurobio.2003.08.002. PMID 14568359. S2CID 12719687.
  22. Fan, Dawei; Krishnamurthi, Rita; 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. doi:10.1002/acn3.743. PMC 6469247. PMID 31019991. S2CID 104430959.
  23. Kang, Dali; Waldvogel, Henry J.; Wang, Ao; Fan, Dawei; Faull, Richard L.M.; Curtis, Maurice A.; Shorten, Paul R.; Guan, Jian (May 2021). "The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer's disease". Psychoneuroendocrinology. 127: 105191. doi:10.1016/j.psyneuen.2021.105191. PMID 33706042. S2CID 232116896.
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