Cyclic glycine-proline

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Cyclic glycine-proline
Cyclo(Gly-Pro).svg
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
PubChem CID
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).

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]

Contents

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). [3] [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). [3] [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. [15]

In vitro studies show that cGP promoted the activity of IGF-1 when insufficient and inhibited the activity of IGF-1 when in excess. [15]

Uses

A recently published review in the journal Marine Drugs, provides an excellent overview of cGP sources and biological effects. [16] 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. [17] Metabolic IGF-1 levels tend to reduce with age and this reduction appears to be a major contributor to cognitive impairment in older populations. [18] [19]

Low or deficient IGF-1 levels can be normalized by cGP, restoring its vascular function. [15] 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. [14]

Hypertension

IGF-1 plays a critical role in energy metabolism with deficient IGF-1 levels being implicated in obesity and hypertension. [20]

Stroke

The role of IGF-1 in supporting recovery from stroke, which is a condition of vascular origin, is reported. [21] [22] 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. [23]

Therapeutic Potential

Excessive IGF-1 activity promotes tumorigenesis [8] while reduced IGF-1 activity is linked with diseases such as Alzheimer's [24] and Parkinson's. [14] 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. [15] Therefore, it is reasonable to assume that treatment with exogenous cGP could assist with improving IGF-1 implicated health benefits. [3]

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<span class="mw-page-title-main">Colostrum</span> Form of milk produced immediately following the delivery of newborn

Colostrum is the first form of milk produced by the mammary glands of humans and other mammals immediately following delivery of the newborn. It may be called beestings, the traditional word from Old English dialects, when referring to the first milk of a cow or other animals. Most species will begin to generate colostrum just prior to giving birth. Colostrum has an especially high amount of bioactive compounds compared to mature milk to give the newborn the best possible start to life. Specifically, colostrum contains antibodies to protect the newborn against disease and infection, and immune and growth factors and other bioactives that help to activate a newborn's immune system, jumpstart gut function, and seed a healthy gut microbiome in the first few days of life. The bioactives found in colostrum are essential for a newborn's health, growth and vitality. Colostrum strengthens a baby's immune system and is filled with white blood cells to protect it from infection.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein found in humans

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

<span class="mw-page-title-main">Insulin-like growth factor 2</span> Protein hormone

Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on somatotropin. It is believed to be a major fetal growth factor in contrast to insulin-like growth factor 1 (IGF-1), which is a major growth factor in adults."

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell receptor protein found in humans

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

<span class="mw-page-title-main">Insulin-like growth factor-binding protein</span> Transport protein for insulin-like growth factor 1

The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).

<span class="mw-page-title-main">Insulin-like growth factor 2 receptor</span> Protein found in humans

Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the IGF2R gene. IGF2R is a multifunctional protein receptor that binds insulin-like growth factor 2 (IGF2) at the cell surface and mannose-6-phosphate (M6P)-tagged proteins in the trans-Golgi network.

Pappalysin-1, also known as pregnancy-associated plasma protein A, and insulin-like growth factor binding protein-4 protease is a protein encoded by the PAPPA gene in humans. PAPPA is a secreted protease whose main substrate is insulin-like growth factor binding proteins. Pappalysin-1 is also used in screening tests for Down syndrome.

<span class="mw-page-title-main">IGFBP3</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes included in this family, shares neither the conserved structural features nor the high IGF affinity. Instead, IGFBP-7 binds IGF1R, which blocks IGF-1 and IGF-2 binding, resulting in apoptosis.

<span class="mw-page-title-main">IGFBP2</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 2 is a protein that in humans is encoded by the IGFBP2 gene.

<span class="mw-page-title-main">IGFBP5</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 5(IBF-5) is a protein that in humans is encoded by the IGFBP5 gene. An IGFBP5 gene was recently identified as being important for adaptation to varying water salinity in fish.

<span class="mw-page-title-main">IGFBP4</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 4 is a protein that in humans is encoded by the IGFBP4 gene.

<span class="mw-page-title-main">IGFBP6</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 6 (IGFBP-6) is a protein that in humans is encoded by the IGFBP6 gene.

<span class="mw-page-title-main">IGFBP1</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the IGFBP1 gene.

<span class="mw-page-title-main">IGFBP7</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with low affinity compared to IGFBPs 1-6. It also stimulates cell adhesion. The protein is implicated in some cancers.

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

Insulin-like growth factor binding protein, acid labile subunit, also known as IGFALS, is a protein which in humans is encoded by the IGFALS gene.

Mecasermin, sold under the brand name Increlex, also known as recombinant human insulin-like growth factor-1 (rhIGF-1), is a recombinant form of human insulin-like growth factor 1 (IGF-I) which is used in the long-term treatment of growth failure and short stature in children with severe primary IGF-I deficiency, for instance due to growth hormone deficiency or Laron syndrome.

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

Anamorelin (INN), also known as anamorelin hydrochloride, is a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) with appetite-enhancing and anabolic effects which is under development by Helsinn Healthcare SA for the treatment of cancer cachexia and anorexia.

Long arginine 3-IGF-1, abbreviated as IGF-1 LR3 or LR3-IGF-1, is a synthetic protein and lengthened analogue of human insulin-like growth factor 1 (IGF-1). It differs from native IGF-1 in that it possesses an arginine instead of a glutamic acid at the third position in its amino acid sequence, and also has an additional 13 amino acids at its N-terminus (MFPAMPLLSLFVN) ("long"), for a total of 83 amino acids. The consequences of these modifications are that IGF-1 LR3 retains the pharmacological activity of IGF-1 as an agonist of the IGF-1 receptor, has very low affinity for the insulin-like growth factor-binding proteins (IGFBPs), and has improved metabolic stability. As a result, it is approximately three times more potent than IGF-1, and possesses a significantly longer half-life of about 20–30 hours.

des(1-3)IGF-1 is a naturally occurring, endogenous protein, as well as drug, and truncated analogue of insulin-like growth factor 1 (IGF-1). des(1-3)IGF-1 lacks the first three amino acids at the N-terminus of IGF-1. As a result of this difference, it has considerably reduced binding to the insulin-like growth factor-binding proteins (IGFBPs) and enhanced potency relative to IGF-1.

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. 1 2 3 4 Tran, Loi Hung (June 19, 2007). "US Patent # 7232798: Neuroprotection and neurogenesis by administering cyclic prolyl glycine". US Patent Trademark Office (Priority date: Nov 13, 2001): Filing date: Nov 12, 2002.
  4. ↑ 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.
  5. ↑ 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.
  6. 1 2 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. 1 2 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. 1 2 3 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. 1 2 3 4 5 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. ↑ 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. 22 (6): 271. doi: 10.3390/md22060271 . ISSN   1660-3397. PMC   11205142 . PMID   38921582.
  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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