Wikipedia

Fatty-acid amide hydrolase 1

(Redirected from Fatty acid amide hydrolase)

"FAAH" redirects here. For other uses, see FAAH (disambiguation).

Fatty-acid amide hydrolase 1 (FAAH)[5] is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993.[6] In humans, it is encoded by the gene FAAH.[7][8][9]

FAAH
Identifiers
AliasesFAAH, fatty acid amide hydrolase, FAAH-1, PSAB
External IDsOMIM: 602935; MGI: 109609; HomoloGene: 68184; GeneCards: FAAH; OMA:FAAH - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2166

14073

Ensembl

ENSG00000117480

ENSMUSG00000034171

UniProt

O00519

O08914

RefSeq (mRNA)

NM_001441

NM_010173

RefSeq (protein)

NP_001432

NP_034303

Location (UCSC)Chr 1: 46.39 – 46.41 MbChr 4: 115.82 – 115.88 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

edit

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[10] In vivo, FAAH is the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs). Members of the FAAs include:

FAAH knockout mice display highly elevated (>15-fold) levels of N-acylethanolamines and N-acyltaurines in various tissues. Because of their significantly elevated anandamide levels, FAAH KOs have an analgesic phenotype, showing reduced pain sensation in the hot plate test, the formalin test, and the tail flick test.[16] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[11]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[17][18][19]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders,[20][21][22] as inhibition produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects by elevated N-acylethanolamines (NAE's) and their activation of cannabinoid receptors.[23]

Inhibitors and inactivators

edit

Activation of the cannabinoid receptor CB1 or CB2 in different tissues, including skin, inhibit FAAH, and thereby increases endocannabinoid levels.[24]

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[25][26][27][28][29][30][31][32]

Some of the more significant compounds are listed below;

Inhibition and binding

edit

Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and stereochemistry of a delta cis double bond.[48]

Enhancement of FAAH activity

edit

Insulin medication increases the production and activity of FAAH.[49]

Genetic variants

edit

rs324420

edit
SNP: rs324420
Name(s)C385A, c.385C>A, p.Pro129Thr
GeneFAAH
Chromosome1
RegionExon
External databases
EnsemblHuman SNPView
dbSNP324420
HapMap324420
SNPedia324420

The FAAH gene contains a single nucleotide polymorphism (SNP) called rs324420. The variant allele, C385A, is associated with a higher sensitivity of FAAH to proteolytic degradation and a shorter half-life compared to the standard C variant. As a result, carriers of the A variant has increased N-acylethanolamine (NAE) levels and anandamide (AEA) signaling at the cannabinoid receptors. The A variant may be responsible for lower levels of the FAAH protein seen in high-performing athletes, providing increased physical and mental fitness.[50] However, among elite Polish athletes, the A variant is under-represented regardless of metabolic characteristics of their sport disciplines; this seems to suggest an opposite role for the A variant.[51]

A 2017 study found a strong correlation between national percentage of very happy people (as measured by the World Values Survey) and the presence of the rs324420 C385A allele in citizens' genetic make-up.[52]

The C385A allele was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies. According to later studies, carriers of the A allele are more likely to try cannabis, but less likely to become dependent.[20]: § 5.6 

FAAH-OUT microdeletion

edit
Main article: Jo Cameron

FAAH-OUT is a pseudogene downstream of the FAAH coding region. It expresses a long non-coding RNA (lncRNA) that increases the expression of FAAH.[53] In 2019, a Scottish woman named Jo Cameron was found to have both a previously unreported microdeletion mutation in FAAH-OUT and a rs324420 C385A mutation. The result is extreme disruption of FAAH function leading to elevated anandamide levels. She was immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts suffered due to her hypoalgesia healed quicker than average with little or no scarring.[54][55][56] Her son, who shares the FAAH-OUT deletion but has no C385A mutation, has a lesser degree of pain insensitivity.[54]

A 2023 study looks further into the functions of FAAH-OUT using transcriptomic analyses of cell models, some created anew using CRISPR-Cas9, others obtained from the 2019 patient. The study confirms that FAAH-OUT increases the expression of FAAH, both via its lncRNA product and through an intronic enhancer called FAAH-AMP. Loss of FAAH-OUT also changes the expression of a wide network of genes beyond FAAH itself. For example, although the pain insensitivity is mostly due to loss of FAAH function (via increased endocannabinoid levels and reduced ACKR3 expression), lack of depression and anxiety is instead due to a non-canonical Wnt pathway upregulating BDNF. The increased wound healing is due to both pathways: loss of FAAH function increases N-acyltaurine levels; the non-canonical Wnt pathway is also beneficial to healing.[53]

Assays

edit

The enzyme is typically assayed making use of a radiolabelled anandamide substrate, which generates free labelled ethanolamine, although alternative LC-MS methods have also been described.[57][58]

Structures

edit

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[9] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[59]

Regulation

edit

In slime molds

edit

The slime mold Dictyostelium discoideum produces a semispecific FAAH inhibitor. By controlling the levels of FAAH activity, they modulate endogenous N-acylethanolamine levels.[23]

Enzyme classification

edit

In the Enzyme Commission numbering scheme, "fatty acid amide hydrolase" is EC 3.5.1.99. The number applies to all enzymes that have the chemical activity; in humans it covers both the genes FAAH and FAAH2. The systematic name is "fatty acylamide amidohydrolase". Recorded synonyms include "oleamide hydrolase", "anandamide amidohydrolase".[60]

See also

edit

References

edit
  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000117480 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034171 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "UniProt". www.uniprot.org. Retrieved 18 July 2023.
  6. ^ Deutsch DG, Chin SA (September 1993). "Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist". Biochemical Pharmacology. 46 (5): 791–796. doi:10.1016/0006-2952(93)90486-G. PMID 8373432.
  7. ^ Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (November 1996). "Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides". Nature. 384 (6604): 83–87. Bibcode:1996Natur.384...83C. doi:10.1038/384083a0. PMID 8900284. S2CID 4288981.
  8. ^ Giang DK, Cravatt BF (March 1997). "Molecular characterization of human and mouse fatty acid amide hydrolases". Proceedings of the National Academy of Sciences of the United States of America. 94 (6): 2238–2242. Bibcode:1997PNAS...94.2238G. doi:10.1073/pnas.94.6.2238. PMC 20071. PMID 9122178.
  9. ^ a b PDB: 1MT5​; Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (November 2002). "Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling". Science. 298 (5599): 1793–1796. Bibcode:2002Sci...298.1793B. doi:10.1126/science.1076535. PMID 12459591. S2CID 22656813.
  10. ^ Patricelli MP, Cravatt BF (October 1999). "Fatty acid amide hydrolase competitively degrades bioactive amides and esters through a nonconventional catalytic mechanism". Biochemistry. 38 (43): 14125–14130. doi:10.1021/bi991876p. PMID 10571985.
  11. ^ a b Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (July 2001). "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase". Proceedings of the National Academy of Sciences of the United States of America. 98 (16): 9371–9376. Bibcode:2001PNAS...98.9371C. doi:10.1073/pnas.161191698. PMC 55427. PMID 11470906.
  12. ^ Ueda N, Puffenbarger RA, Yamamoto S, Deutsch DG (November 2000). "The fatty acid amide hydrolase (FAAH)". Chemistry and Physics of Lipids. 108 (1–2): 107–121. doi:10.1016/S0009-3084(00)00190-0. PMID 11106785.
  13. ^ Saghatelian A, Trauger SA, Want EJ, Hawkins EG, Siuzdak G, Cravatt BF (November 2004). "Assignment of endogenous substrates to enzymes by global metabolite profiling". Biochemistry. 43 (45): 14332–14339. CiteSeerX 10.1.1.334.206. doi:10.1021/bi0480335. PMID 15533037.
  14. ^ Cravatt BF, Prospero-Garcia O, Siuzdak G, Gilula NB, Henriksen SJ, Boger DL, Lerner RA (June 1995). "Chemical characterization of a family of brain lipids that induce sleep". Science. 268 (5216): 1506–1509. Bibcode:1995Sci...268.1506C. doi:10.1126/science.7770779. PMID 7770779.
  15. ^ Saghatelian A, McKinney MK, Bandell M, Patapoutian A, Cravatt BF (August 2006). "A FAAH-regulated class of N-acyl taurines that activates TRP ion channels". Biochemistry. 45 (30): 9007–9015. doi:10.1021/bi0608008. PMID 16866345.
  16. ^ Cravatt BF, Lichtman AH (October 2004). "The endogenous cannabinoid system and its role in nociceptive behavior". Journal of Neurobiology. 61 (1): 149–160. doi:10.1002/neu.20080. PMID 15362158.
  17. ^ Sałaga M, Sobczak M, Fichna J (February 2014). "Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract". European Journal of Pharmaceutical Sciences. 52: 173–179. doi:10.1016/j.ejps.2013.11.012. PMID 24275607.
  18. ^ Ulugöl A (June 2014). "The endocannabinoid system as a potential therapeutic target for pain modulation". Balkan Medical Journal. 31 (2): 115–120. doi:10.5152/balkanmedj.2014.13103. PMC 4115931. PMID 25207181.
  19. ^ Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, et al. (August 2015). "Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice". The Journal of Pharmacology and Experimental Therapeutics. 354 (2): 111–120. doi:10.1124/jpet.115.222851. PMC 4518073. PMID 25998048.
  20. ^ a b Panlilio LV, Justinova Z, Goldberg SR (April 2013). "Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction". Pharmacology & Therapeutics. 138 (1): 84–102. doi:10.1016/j.pharmthera.2013.01.003. PMC 3662489. PMID 23333350.
  21. ^ Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A (November 2013). "Amygdala FAAH and anandamide: mediating protection and recovery from stress". Trends in Pharmacological Sciences. 34 (11): 637–644. doi:10.1016/j.tips.2013.08.008. PMC 4169112. PMID 24325918.
  22. ^ Berardi A, Schelling G, Campolongo P (September 2016). "The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings". Pharmacological Research. 111: 668–678. doi:10.1016/j.phrs.2016.07.024. PMID 27456243.
  23. ^ a b Hayes AC, Stupak J, Li J, Cox AD (February 2013). "Identification of N-acylethanolamines in Dictyostelium discoideum and confirmation of their hydrolysis by fatty acid amide hydrolase". Journal of Lipid Research. 54 (2): 457–466. doi:10.1194/jlr.M032219. PMC 3588872. PMID 23187822.
  24. ^ Shin KO, Kim S, Park BD, Uchida Y, Park K (August 2021). "N-Palmitoyl Serinol Stimulates Ceramide Production through a CB1-Dependent Mechanism in In Vitro Model of Skin Inflammation". International Journal of Molecular Sciences. 22 (15): 8302. doi:10.3390/ijms22158302. PMC 8348051. PMID 34361066.
  25. ^ Janero DR, Vadivel SK, Makriyannis A (April 2009). "Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders: drug-discovery strategies". International Review of Psychiatry. 21 (2): 122–133. doi:10.1080/09540260902782778. PMC 5531754. PMID 19367506.
  26. ^ Ahn K, Johnson DS, Cravatt BF (July 2009). "Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders". Expert Opinion on Drug Discovery. 4 (7): 763–784. doi:10.1517/17460440903018857. PMC 2882713. PMID 20544003.
  27. ^ Petrosino S, Di Marzo V (January 2010). "FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels". Current Opinion in Investigational Drugs. 11 (1): 51–62. PMID 20047159.
  28. ^ Minkkilä A, Saario S, Nevalainen T (2010). "Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors". Current Topics in Medicinal Chemistry. 10 (8): 828–858. doi:10.2174/156802610791164238. PMID 20370710.
  29. ^ Khanna IK, Alexander CW (August 2011). "Fatty acid amide hydrolase inhibitors--progress and potential". CNS & Neurological Disorders Drug Targets. 10 (5): 545–558. doi:10.2174/187152711796234989. PMID 21631410.
  30. ^ Bisogno T, Maccarrone M (May 2013). "Latest advances in the discovery of fatty acid amide hydrolase inhibitors". Expert Opinion on Drug Discovery. 8 (5): 509–522. doi:10.1517/17460441.2013.780021. PMID 23488865. S2CID 33195822.
  31. ^ Pertwee RG (February 2014). "Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications". The Proceedings of the Nutrition Society. 73 (1): 96–105. doi:10.1017/S0029665113003649. PMID 24135210.
  32. ^ Lodola A, Castelli R, Mor M, Rivara S (2015). "Fatty acid amide hydrolase inhibitors: a patent review (2009-2014)". Expert Opinion on Therapeutic Patents. 25 (11): 1247–1266. doi:10.1517/13543776.2015.1067683. PMID 26413912. S2CID 41218277.
  33. ^ Enserink M (2016). "More Details Emerge on Fateful French Drug Trial" (online). Science (January 16). doi:10.1126/science.aae0247. Retrieved 16 January 2016.
  34. ^ Blankman JL, Cravatt BF (April 2013). "Chemical probes of endocannabinoid metabolism". Pharmacological Reviews. 65 (2): 849–871. doi:10.1124/pr.112.006387. PMC 3639726. PMID 23512546.
  35. ^ Min X, Thibault ST, Porter AC, Gustin DJ, Carlson TJ, Xu H, et al. (May 2011). "Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)". Proceedings of the National Academy of Sciences of the United States of America. 108 (18): 7379–7384. Bibcode:2011PNAS..108.7379M. doi:10.1073/pnas.1016167108. PMC 3088576. PMID 21502526.
  36. ^ Keith JM, Jones WM, Tichenor M, Liu J, Seierstad M, Palmer JA, et al. (December 2015). "Preclinical Characterization of the FAAH Inhibitor JNJ-42165279". ACS Medicinal Chemistry Letters. 6 (12): 1204–1208. doi:10.1021/acsmedchemlett.5b00353. PMC 4677372. PMID 26713105.
  37. ^ "Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders". Janssen.com. 17 January 2016. Archived from the original on 25 January 2016. Retrieved 21 January 2016.
  38. ^ Moore SA, Nomikos GG, Dickason-Chesterfield AK, Schober DA, Schaus JM, Ying BP, et al. (December 2005). "Identification of a high-affinity binding site involved in the transport of endocannabinoids". Proceedings of the National Academy of Sciences of the United States of America. 102 (49): 17852–17857. doi:10.1073/pnas.0507470102. PMC 1295863. PMID 16314570.
  39. ^ Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). "Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 367 (1607): 3364–3378. doi:10.1098/rstb.2011.0389. PMC 3481531. PMID 23108553.
  40. ^ a b Ahn K, Johnson DS, Fitzgerald LR, Liimatta M, Arendse A, Stevenson T, et al. (November 2007). "Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity". Biochemistry. 46 (45): 13019–13030. doi:10.1021/bi701378g. PMID 17949010.
  41. ^ Fowler CJ (2015). "The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review". Endocannabinoids. Handbook of Experimental Pharmacology. Vol. 231. pp. 95–128. doi:10.1007/978-3-319-20825-1_4. ISBN 978-3-319-20824-4. PMID 26408159.
  42. ^ Clinical trial number NCT00822744 for "An Eight-week Study of SSR411298 as Treatment for Major Depressive Disorder in Elderly Patients (FIDELIO)" at ClinicalTrials.gov
  43. ^ "Clinical trials for SSR411298". EU Clinical Trials Register.
  44. ^ Hart T, Macias AT, Benwell K, Brooks T, D'Alessandro J, Dokurno P, et al. (August 2009). "Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas". Bioorganic & Medicinal Chemistry Letters. 19 (15): 4241–4244. doi:10.1016/j.bmcl.2009.05.097. PMID 19515560.
  45. ^ Clinical trial number NCT01748695 for "A Safety, Tolerability and Efficacy Study of V158866 in Central Neuropathic Pain Following Spinal Cord Injury" at ClinicalTrials.gov
  46. ^ US granted 8450346, Roughly S, Walls S, Hart T, Parsons R, Brough P, Graham C, Macias A, "Azetidine derivatives as FAAH inhibitors", published 28 May 2013, assigned to Vernalis (R&D) Ltd. 
  47. ^ Roughley SD, Browne H, Macias AT, Benwell K, Brooks T, D'Alessandro J, et al. (January 2012). "Fatty acid amide hydrolase inhibitors. 3: tetra-substituted azetidine ureas with in vivo activity". Bioorganic & Medicinal Chemistry Letters. 22 (2): 901–906. doi:10.1016/j.bmcl.2011.12.032. PMID 22209458.
  48. ^ Boger DL, Sato H, Lerner AE, Austin BJ, Patterson JE, Patricelli MP, Cravatt BF (January 1999). "Trifluoromethyl ketone inhibitors of fatty acid amide hydrolase: a probe of structural and conformational features contributing to inhibition". Bioorganic & Medicinal Chemistry Letters. 9 (2): 265–270. doi:10.1016/S0960-894X(98)00734-3. PMID 10021942.
  49. ^ Weis F (2010). "Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery". British Journal of Anaesthesia. 105 (2): 139–144. doi:10.1093/bja/aeq117. PMID 20525978.
  50. ^ Silva HH, Tavares V, Silva MG, Neto BV, Cerqueira F, Medeiros R (May 2023). "Association of FAAH rs324420 (C385A) Polymorphism with High-Level Performance in Volleyball Players". Genes. 14 (6): 1164. doi:10.3390/genes14061164. PMC 10298391. PMID 37372343.
  51. ^ Peplonska B, Adamczyk JG, Siewierski M, Safranow K, Maruszak A, Sozanski H, et al. (August 2017). "Genetic variants associated with physical and mental characteristics of the elite athletes in the Polish population". Scandinavian Journal of Medicine & Science in Sports. 27 (8): 788–800. doi:10.1111/sms.12687. PMID 27140937.
  52. ^ Minkov M, Bond MH (2017-04-01). "A Genetic Component to National Differences in Happiness". Journal of Happiness Studies. 18 (2): 321–340. doi:10.1007/s10902-015-9712-y. ISSN 1573-7780. S2CID 54717193.
  53. ^ a b Mikaeili H, Habib AM, Yeung CW, Santana-Varela S, Luiz AP, Panteleeva K, et al. (September 2023). "Molecular basis of FAAH-OUT-associated human pain insensitivity". Brain. 146 (9): 3851–3865. doi:10.1093/brain/awad098. hdl:10576/44602. PMC 10473560. PMID 37222214.
  54. ^ a b Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, et al. (August 2019). "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia. 123 (2): e249–e253. doi:10.1016/j.bja.2019.02.019. PMC 6676009. PMID 30929760.
  55. ^ Murphy H (28 March 2019). "At 71, She's Never Felt Pain or Anxiety. Now Scientists Know Why". The New York Times. Retrieved 29 March 2019.
  56. ^ Sample I (28 March 2019). "Scientists find genetic mutation that makes woman feel no pain". The Guardian. Retrieved 29 March 2019.
  57. ^ Wang Y, Jones P (2009). "A scintillation proximity assay for fatty acid amide hydrolase compatible with inhibitor screening". Ligand-Macromolecular Interactions in Drug Discovery. Methods in Molecular Biology. Vol. 572. pp. 247–59. doi:10.1007/978-1-60761-244-5_16. ISBN 978-1-60761-243-8. PMID 20694697.
  58. ^ Han B, Wright R, Kirchhoff AM, Chester JA, Cooper BR, Davisson VJ, Barker E (January 2013). "Quantitative LC-MS/MS analysis of arachidonoyl amino acids in mouse brain with treatment of FAAH inhibitor". Analytical Biochemistry. 432 (2): 74–81. doi:10.1016/j.ab.2012.09.031. PMC 3760509. PMID 23044255.
  59. ^ PDB: 2VYA​; Mileni M, Johnson DS, Wang Z, Everdeen DS, Liimatta M, Pabst B, et al. (September 2008). "Structure-guided inhibitor design for human FAAH by interspecies active site conversion". Proceedings of the National Academy of Sciences of the United States of America. 105 (35): 12820–12824. Bibcode:2008PNAS..10512820M. doi:10.1073/pnas.0806121105. PMC 2529035. PMID 18753625.
  60. ^ "KEGG ENZYME: 3.5.1.99". www.genome.jp.
edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fatty-acid_amide_hydrolase_1&oldid=1240560628"