Peptide

CyclicPepedia Knowledge Base

Visitor
Visitor
Status Profile

Insulin Detemir

Basic information

CPKB ID CP01059
IUPAC Name
(2S)-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[2-[[(1R,6R,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,50S,53S,56S,59S,62S,65S,68S,71S,74R,77S,80S,83S,88R)-88-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3S)-2-[(2-aminoacetyl)amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]-6-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-methylpentanoyl]amino]-47-[[(1S)-3-amino-1-carboxy-3-oxopropyl]carbamoyl]-53-(2-amino-2-oxoethyl)-62-(3-amino-3-oxopropyl)-77-[(2S)-butan-2-yl]-24,56-bis(2-carboxyethyl)-83-[(1R)-1-hydroxyethyl]-12,71,80-tris(hydroxymethyl)-33,50,65-tris[(4-hydroxyphenyl)methyl]-15-(1H-imidazol-4-ylmethyl)-27-methyl-18,30,36,59,68-pentakis(2-methylpropyl)-7,10,13,16,19,22,25,28,31,34,37,40,49,52,55,58,61,64,67,70,73,76,79,82,85,87-hexacosaoxo-21,39-di(propan-2-yl)-3,4,44,45,90,91-hexathia-8,11,14,17,20,23,26,29,32,35,38,41,48,51,54,57,60,63,66,69,72,75,78,81,84,86-hexacosazabicyclo[72.11.7]dononacontane-42-carbonyl]amino]acetyl]amino]-4-carboxybutanoyl]amino]-5-carbamimidamidopentanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-6-(tetradecanoylamino)hexanoic acid
Synonyms
169148-63-4
29(Sup-B)-(N(Sup-6)-(1-Oxotetradecyl)-L-Lysine)-(1(Sup-A)-21(Sup-A)),(1(Sup-B)-29(Sup-B))-Insulin-(Human)
29(Sup-B)-(N(Sup-6)-Myristoyl-L-Lysine)-30(Sup-B)-De-L-Threonineinsulin-(Human)
29B-(N6-Myristoyl-L-Lysine)-30B-De-L-Threonineinsulin-(Human)
4Ft78T86Xv
Chembl2104391
Detemir
Insulin-Detemir
Insulin-Detemir-[Usan:Inn:Ban]
Insulin-Detemir-Recombinant
Insulin,Detemir,Human
Levemir
Levemir-Flexpen
Levemir-Innolet
Levemir-Insulin
Levemir-Penfill
Nn304
Nn-304
Unii-4Ft78T86Xv
Family

Peptide hormones   DrugBank  

Function

Insulin, long-acting   DrugBank  

Information

A recombinant long-acting insulin and HYPOGLYCEMIC AGENT in which a MYRISTIC ACID is conjugated to a LYSINE at position B29. It is used to manage BLOOD GLUCOSE levels in patients with DIABETES MELLITUS. A specific streptogramin group A antibiotic produced by Streptomyces graminofaciens and other bacteria.

PubChem|16137271   DrugBank|DB01307  

Legend

Structure

Download structure
2D img
300x300 pixels
100x100 pixels
500x500 pixels
similarity structure
Molecular Formula

C267H402N64O76S6
Molecular Weight 5912.788336 g/mol
SMILES

RUN SEA Predictions

 CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H]2CSSC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N2)[C@@H](C)O)C(=O)O  

PubChem|16137271
InChI
InChI=1S/C267H402N64O76S6/c1-29-32-33-34-35-36-37-38-39-40-50-64-204(347)280-95-52-51-61-170(265(404)405)298-256(395)197-63-54-97-331(197)264(403)220(147(28)336)330-248(387)182(110-154-71-79-160(340)80-72-154)309-240(379)178(106-150-59-48-43-49-60-150)307-237(376)177(105-149-57-46-42-47-58-149)289-207(350)120-282-223(362)162(62-53-96-281-267(276)277)291-227(366)163(84-91-209(352)353)288-206(349)119-283-225(364)192-126-409-410-127-193(252(391)314-187(266(406)407)115-203(275)346)319-241(380)181(109-153-69-77-159(339)78-70-153)308-245(384)185(113-201(273)344)312-231(370)168(86-93-211(356)357)295-233(372)172(99-134(6)7)300-229(368)164(81-88-198(270)341)293-238(377)179(107-151-65-73-157(337)74-66-151)305-235(374)173(100-135(8)9)304-250(389)189(123-333)315-253(392)195-129-412-411-128-194(318-232(371)166(83-90-200(272)343)292-228(367)169(87-94-212(358)359)297-258(397)216(142(22)23)327-262(401)217(143(24)30-2)323-205(348)116-268)254(393)320-196(255(394)329-219(146(27)335)263(402)316-190(124-334)251(390)328-218(144(25)31-3)261(400)322-195)130-413-408-125-191(317-236(375)174(101-136(10)11)301-242(381)183(111-155-117-278-131-285-155)310-230(369)165(82-89-199(271)342)294-244(383)186(114-202(274)345)313-259(398)213(139(16)17)324-222(361)161(269)104-148-55-44-41-45-56-148)224(363)284-121-208(351)290-188(122-332)249(388)311-184(112-156-118-279-132-286-156)243(382)303-176(103-138(14)15)247(386)325-214(140(18)19)257(396)296-167(85-92-210(354)355)226(365)287-145(26)221(360)299-171(98-133(4)5)234(373)306-180(108-152-67-75-158(338)76-68-152)239(378)302-175(102-137(12)13)246(385)326-215(141(20)21)260(399)321-192/h41-49,55-60,65-80,117-118,131-147,161-197,213-220,332-340H,29-40,50-54,61-64,81-116,119-130,268-269H2,1-28H3,(H2,270,341)(H2,271,342)(H2,272,343)(H2,273,344)(H2,274,345)(H2,275,346)(H,278,285)(H,279,286)(H,280,347)(H,282,362)(H,283,364)(H,284,363)(H,287,365)(H,288,349)(H,289,350)(H,290,351)(H,291,366)(H,292,367)(H,293,377)(H,294,383)(H,295,372)(H,296,396)(H,297,397)(H,298,395)(H,299,360)(H,300,368)(H,301,381)(H,302,378)(H,303,382)(H,304,389)(H,305,374)(H,306,373)(H,307,376)(H,308,384)(H,309,379)(H,310,369)(H,311,388)(H,312,370)(H,313,398)(H,314,391)(H,315,392)(H,316,402)(H,317,375)(H,318,371)(H,319,380)(H,320,393)(H,321,399)(H,322,400)(H,323,348)(H,324,361)(H,325,386)(H,326,385)(H,327,401)(H,328,390)(H,329,394)(H,330,387)(H,352,353)(H,354,355)(H,356,357)(H,358,359)(H,404,405)(H,406,407)(H4,276,277,281)/t143-,144-,145-,146+,147+,161-,162-,163-,164-,165-,166-,167-,168-,169-,170-,171-,172-,173-,174-,175-,176-,177-,178-,179-,180-,181-,182-,183-,184-,185-,186-,187-,188-,189-,190-,191-,192-,193-,194-,195-,196-,197-,213-,214-,215-,216-,217-,218-,219-,220-/m0/s1  
InChIKey
UGOZVNFCFYTPAZ-RKPXRJJGNA-N
2D Structure
PubChem|16137271

Sequence

Graph alignment
IUPAC Condensed
H-Phe-Val-Asn-Gln-His-Leu-Cys(1)-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys(2)-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys(myristoyl)-OH.H-Gly-Ile-Val-Glu-Gln-Cys(3)-Cys(1)-Thr-Ser-Ile-Cys(3)-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys(2)-Asn-OH  

PubChem|16137271
Amino acid chain from Structure
Lys--Pro--Thr--Tyr--Phe--Phe--Gly--Orn--Glu--Gly--Cys(1)--Val--Leu--Tyr--Leu--Ala--Glu--Val--Leu--His--Ser--Gly--Cys(2)--Leu--His--Gln--Asn--Val--Phe--Asn--Cys(1)--Tyr--Asn--Glu--Leu--Gln--Tyr--Leu--Ser--Cys(3)--Ile--Ser--Thr--Cys(2)--Cys(3)--Gln--Glu--Val--Ile--Gly  

CyclicPepedia|Struct2seq
svg Image

PubChem|16137271

Chemical and Physical Properties

Structure Properties

Property Name Property Value
Exact Mass 5912.788336
Number of Rings 12.0
Complexity 0.227602906
XlogP3 AA -13.37933
Heavy Atom Count 413.0
Hydrogen Bond Donor Count 76.0
Hydrogen Bond Acceptor Count 81.0
Rotatable Bond Count 136.0
Property Name Property Value
Formal Charge 0.0
Refractivity 1504.602
Rule_of_Five 0.0
Number of Atoms 413.0
Topological Polar Surface Area 2252.82
Refractivity 1504.602
Veber Rule 0.0
Ghose Filter 0.0
Property Name Property Value
RDKit Fingerprint
11101111111000111100111011111000110001100111110001111010111001101110101111101111111111010110110010010111100001001111011000110010010001011110110100011111110110010101001110100111100110001111100111110110101001001000010110000101010101000101011110011110011110101111001110001000001010001001110000100010111010011011101111010001011100000011111011110110111100011010111101001001101010000010111101100010010100000100100110101111001011100100101001111011111011100100101100010110111000110101100100001010001111010101100000101111110001110110111111011101101110101100111010010110111101101110010110001101000010111100101110111001111010011000100000001111111100111100001111110111111011000110011110100101010111011101011100111011101101100001110111111011001001111001101010111010001110101011111110011000000001100001001010011000001111111011110100101101111011111010011111111101011000110011111100110001010100100100111000011011101101111010111001010110011110111110010001011111101010001111111101010000011001010110001111111011110101000111010000111101001111110011110111111011100000001011010101001110101101100111111011011101110110101001001111011110000000101111100111001011110111011100111011111000101110100110101111011011010011101111111011001101100101001111110111100110011100110111011110010000111111001110101000001100110001111000110101111001011110100101000001110111101001011011111110011011011110110011010000010010101101011000001010000111110101011100100011000101101011111010011011111110001101101011101100111110111001100001111010111111111011010100110100100111010011110000001001110101111110100100110011101000101110100111101001011111100010000001010111100011010010100010110000010100100000111110010010011001001011010101101010101101000110110111111110100100110101000011010111101001100000110111011001010111110110010110101010001010101001010110100011010011111101101100100011111010011111100111110011001011100001010100111111100101010100001101101110011111101101100111010010010111011011011111110110100011111001011011001011000011001101100111101101001100110010011000001011101110000100110100111100010111
Morgan Fingerprint
0100100000100000000000000001010001001000011000010000010000100000100000000000000110000010001000100000011000001100000101010100000010100000000010010001000000000000000000000000010100000000000000000110010000010000000000001000101000010000000000000011000000100100000100010010100000000000001101000100001000000100000000100010000001000000000000010000000100000100001110000010000001000000101000000001010001000000001000000000000010001000000110001001100010000010000000001110000000000000000000100010000010001100000000010011011000000001100000000001000000001000010000010000000000000100000011010010000000000001101001001000000011000000100000011100000000000000000000000010000000000000010101000001000010001001011100110100000000001000010100000000101010110010100100000100010000100001010000010000000000000000001000000010001100001001000000000000100101001000110001001010001001001001010000001000000000110000000000010010011100010000000000000000010000000010000100010000000000000000011101000000001000000000100001111000000010000000000010000000000101010000
MACCS Keys
00000000000000100000000001000000000010000001000000000110000000000101000000110111101111001111100111001000111011110111111111111101111111001111111101111111111111111111110

Binding Target

Detail

Uniprot:  P06213

Kind:  Protein>Insulin receptor

Organism:  Homo sapiens(Human)

Evidevce:  DrugBank

Sequence:  MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNEECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGCTVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSNPS

General Function:

      Receptor signaling protein tyrosine kinase activity

Specific Function:

      Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.

Additional database information: TTD[Insulin receptor]

Detail

Uniprot:  P08069

Kind:  Protein>Growth factor receptor

Organism:  Homo sapiens(Human)

Evidevce:  DrugBank

Sequence:  MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLENCTVIEGYLHILLISKAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIFEMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTVDWSLILDAVSNNYIVGNKPPKECGDLCPGTMEEKPMCEKTTINNEYNYRCWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCSAPDNDTACVACRHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHDGECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQMLQGCTIFKGNLLINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFLKNLRLILGEEQLEGNYSFYVLDNQNLQQLWDWDHRNLTIKAGKMYFAFNPKLCVSEIYRMEEVTGTKGRQSKGDINTRNNGERASCESDVLHFTSTTTSKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDGQDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSEILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQPQDGYLYRHNYCSKDKIPIRKYADGTIDIEEVTENPKTEVCGGEKGPCCACPKTEAEKQAEKEEAEYRKVFENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTAADTYNITDPEELETEYPFFESRVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFARTMPAEGADDIPGPVTWEPRPENSIFLKWPEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGNYTARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHRKRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKGVVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQPTLVIMELMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARNCMVAEDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSFGVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSSTC

General Function:

      Protein tyrosine kinase activity

Specific Function:

      Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.

Additional database information: TTD[Insulin-like growth factor 1 receptor]

Other evidence

Property Name Property ID
TTD D0QE5U
DrugMAP DMOA4VW

Biologic Description

Drug Indication PubChem|16137271

Insulin detemir is indicated to improve glycemic control in adults and children with diabetes mellitus.

Pharmacology PubChem|16137271

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by the liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin.

Toxicity PubChem|16137271

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness.Individuals may become unconscious in severe cases of hypoglycemia. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

Metabolism PubChem|16137271

The liver and kidney play the major role in metabolizing insulin.However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system.

Manufacturers

Manufacturers Name Value
CreativePeptides
Bayer healthcare pharmaceuticals
Upsher smith laboratories
Merck
Manufacturers Name Value
Apotex
Baxter Healthcare Corp
Pharmasources
Novartis
AstraZeneca

Forecasting tools

Forecasting tools Value
Structure to Sequence
CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H]2CSSC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N2)[C@@H](C)O)C(=O)O
Structure Properties
CCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(=O)O)NC(=O)CNC(=O)[C@@H]1CSSC[C@@H](C(=O)N[C@@H](CC(N)=O)C(=O)O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H]2CSSC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc3c[nH]cn3)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc3ccccc3)C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](Cc3c[nH]cn3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N2)[C@@H](C)O)C(=O)O
Expasy ProtParam Tool
SEA RUN SEA Predictions

Information Source

Reference

Pubmed_ID Title DOI Journal

8175045

 Comparison of in vitro and in vivo properties of rhirudin (HBW 023) and a synthetic analogous peptide 10.1159/000216883.

Haemostasis

Comparison of in vitro and in vivo properties of rhirudin (HBW 023) and a synthetic analogous peptide

Abstract

  • Recombinant hirudin and a shortened synthetic analogue, with the amino acid sequence of D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu- Glu-Ile-Pro-Glu-Glu-Tyr-Leu, are specific thrombin inhibitors which in a concentration-dependent manner inhibit thrombus formation as well as clot propagation both in vitro and in vivo. In comparison to the analogue, lower molar concentrations of rhirudin affected doubling of aPTT and TT as well as inhibition of thrombin amidolytic activity or thrombin-induced platelet aggregation in vitro. In the rat wire coil-induced thrombosis model, a 50% thromboprotective effect may be brought about with doses of 0.043 mumol/kg of rhirudin and 1.43 mumol/kg of the synthetic peptide. However, doubling of bleeding times is caused, on average, by dosages of between 0.143 and 0.43 mumol/kg rhirudin or approximately 0.143 mumol/kg of the analogue. Treatment groups included animals revealing significant prolongation of bleeding times as well as nonresponders. Despite the 10-fold longer impact on aPTT after application of rhirudin, the extent of mean bleeding time prolongation is identical to that of the analogue.

8211886

 Leukotriene formation by peripheral monocytes in contact-activated human blood 10.1016/0049-3848(93)90093-4.

Thromb Res

Leukotriene formation by peripheral monocytes in contact-activated human blood

Abstract

  • Contact activation of the intrinsic coagulation cascade in whole human blood in vitro has previously been demonstrated to trigger release of leukotrienes (LT) into serum samples. In our present study we intended to identify the cellular origin of the activated 5-lipoxygenase pathway leading to LT formation under these experimental conditions. Therefore, whole human blood samples incubated for 60 min in vitro were supplemented with Percoll-isolated, 5-lipoxygenase-carrying, autologous blood cells. Surprisingly, exogenously added polymorphonuclear neutrophils (PMN, 5 x 10(6) or 15 x 10(6)/ml) capable of producing cysteinyl-LT in response to ionophore A23187 (1 microM) stimulation, had no effect neither on immunoreactive cysteinyl-LT nor on thromboxane (TX) B2 formation. However, exogenously added mononuclear cells (MNC, 5 x 10(6) or 15 x 10(6)/ml) led to a cell number-dependent increase in cysteinyl-LT generation as did supplementation with peripheral monocytes (PM, 5 x 10(5) or 15 x 10(5)/ml). While MNC enhanced the TXB2 production, PM had no such effect. Incubation of PM (5 x 10(5) or 15 x 10(5)/ml) in recalcified platelet-rich plasma (PRP) induced a cysteinyl-LT formation comparable to that in whole human blood. In contrast to the TXB2 generation, the cysteinyl-LT formation appears to be largely independent from thrombin, since recombinant hirudin (HBW 023, 2 microM), a specific thrombin inhibitor, had no significant effect on the cysteinyl-LT production but nearly completely abolished the TXB2 formation. By reverse phase HPLC the immunoreactive cysteinyl-LT were shown to consist of a mixture of LTC4, LTD4 and LTE4, with LTC4 being the predominant metabolite in all samples studied.(ABSTRACT TRUNCATED AT 250 WORDS)