3-인도레프로피온산

3-Indolepropionic acid
3-도레프로피온산
3-Indolepropionic acid skeletal.svg
임상자료
상명옥시공[2]
기타 이름콘게이트 산:
• 1H-Indole-3-propanoic acid
• 인도레-3 프로피온산
결합 기준:
• 인도레-3-제안
ATC 코드
  • 없는
법적현황
법적현황
  • US: 미예정
  • UN: 미예정
식별자
  • 3-(1H-인돌-3-yl)프로파노산
CAS 번호
펍켐 CID
IUPHAR/BPS
켐스파이더
유니
체비
CompTox 대시보드 (EPA)
ECHA InfoCard100.011.455 Edit this at Wikidata
화학 및 물리적 데이터
공식C11H11NO2
어금질량189.214 g·190−1
3D 모델(JSmol)
녹는점134~135°C(273~275°F)
  • C1=CC=C2C(=C1)C(=CN2)CC(=O)o
  • InChi=1S/C11H11NO2/c13-11(14)6-8-7-12-10-4-2-3-9(8)10/h1-4,7,12H,5-6H2,(H,13,14)
  • 키:GOLXRNDWANDYKT-UHFFFAOYSA-N
(iii)

3-Indolepionic acid(IPA) 또는 insurle-3-propionic acid는 알츠하이머병 치료용으로 연구되고 있는 인간의 강력한 신경보호성 항산화제, 식물 보조제, 자연산이다.[2][3][4][5] 인간의 마이크로바이오타에 의해 내생적으로 생성되며, 종인 클로스트리디움 산포체가 위장관에 존재할 때만 체내 검출되었다.[4][5][6] 2016년 4월 현재 트립토판을 사용하여 IPA를 합성하는 C. 산포체는 숙주의 혈장에서 검출 가능한 수준으로 생체내 IPA를 합성하는 것으로 알려진 유일한 박테리아 종이다.[4][5][6][7]

IPA는 인간 효소에 의해 합성되는 가장 강력한 히드록실산소 스캐빈저인 멜라토닌보다 훨씬 더 강력한 히드록실산소 스캐빈저다.[3][7] 멜라토닌과 유사하지만 다른 산화방지제와 달리 활성산소와 친산화 중간 화합물을 생성하지 않고 활성산소를 제거한다.[3][7][8] 2017년 인간 혈장 내 IPA 농도 상승은 제2형 당뇨병의 위험성이 낮고 섬유질이 풍부한 식품의 섭취가 증가하면서 상관관계가 있는 것으로 나타났다.[3][9][10]

사람의 생합성 및 세포 효과

인간의 위장 미생물(microbiota)에 의한 트립토판 대사.
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이 도표는 내장의 박테리아에 의한 트립토판으로부터 생체활성화 화합물(도 및 기타 특정 파생상품)의 생합성을 보여준다.[5] 인도일은 트립토파나제를 나타내는 박테리아에 의해 트립토판으로부터 생산된다.[5]클로스트리디움 산포체는 트립토판을 세굴로 대사하고 그 후 히드록실산소를 파내는 강력한 신경보호제인 [4]3-인돌프로피온산(IPA)을 투여한다.[5][3][7] IPA는 장세포의 임신 X 수용체(PXR)에 결합해 점막동맥경화와 장벽 기능을 촉진한다.[5] IPA는 장에서 흡수되어 뇌로 전달된 후 뇌허혈과 알츠하이머병에 대해 신경보호 효과를 부여한다.[5]유산균종은 트립토판을 장내 면역세포에서 아릴 탄화수소 수용체(AhR)에 작용하는 인둘레-3알데히드(I3A)로 대사시켜 인터루킨-22(IL-22) 생성을 증가시킨다.[5] 인도글 자체가 장내 L세포에서 글루카곤 유사펩타이드-1(GLP-1) 분비를 유발하고 AhR의 리간드 역할을 한다.[5] 또한 인도일은 간에서 인닥실 황산염으로 대사될 수 있는데, 이 화합물은 고농도에서 독성이 있고 혈관질환과 신장기능장애와 관련이 있다.[5] 입으로 섭취하는 장내 흡착제 AST-120(활성 활성탄)은 혈장 내 인닥실 황산염 농도를 감소시킨다.[5]

신진대사

IPA는 간이나 신장에서 3-인도로아크릴산으로 변환될 수 있으며, 이후 글리신과 결합하여 인도lylacryloyl glycine을 형성한다.[11]

역사

IPA의 신경보호제, 항산화제, 항아밀로이드 성질은 1999년 7월 사우스앨라배마 대학의 파폴라 박사와 포에겔러 박사가 이끄는 조사단에 의해 처음 보고되었다.[7][12][13][14]

참고 항목

참조

  1. ^ Galligan JJ (February 2018). "Beneficial actions of microbiota-derived tryptophan metabolites". Neurogastroenterology and Motility. 30 (2): e13283. doi:10.1111/nmo.13283. PMID 29341448. S2CID 39904059.
  2. ^ a b Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA, Chain DG (October 2002). "Development of indole-3-propionic acid (OXIGON) for Alzheimer's disease". Journal of Molecular Neuroscience. 19 (1–2): 213–7. doi:10.1007/s12031-002-0036-0. PMID 12212784. S2CID 31107810. The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer's disease. Indole-3-propionic acid (IPA, OXIGON) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer's disease.
  3. ^ a b c d e f g "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018. Indole-3-propionate (IPA), a deamination product of tryptophan formed by symbiotic bacteria in the gastrointestinal tract of mammals and birds. 3-Indolepropionic acid has been shown to prevent oxidative stress and death of primary neurons and neuroblastoma cells exposed to the amyloid beta-protein in the form of amyloid fibrils, one of the most prominent neuropathologic features of Alzheimer's disease. 3-Indolepropionic acid also shows a strong level of neuroprotection in two other paradigms of oxidative stress. (PMID 10419516) ... More recently it has been found that higher indole-3-propionic acid levels in serum/plasma are associated with reduced likelihood of type 2 diabetes and with higher levels of consumption of fiber-rich foods (PMID 28397877)
    Origin: • Endogenous • Microbial     {{cite web}}: 외부 링크 위치 quote= (도움말)
  4. ^ a b c d Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi:10.1073/pnas.0812874106. PMC 2656143. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes. ... Conversely, a different set of enteric bacteria has been implicated in the metabolic transformation of indole to indole-3-propionic acid (IPA) (27). IPA, also identified only in the plasma of conv mice, has been shown to be a powerful antioxidant (28) ... Although the presence of IPA in mammals has long been ascribed in the literature to bacterial metabolic processes, this conclusion was based on either the production of IPA in ex vivo cultures of individual bacterial species (31) or observed decreases in IPA levels in animals after administration of antibiotics (32). In our own survey of IPA production by representative members of the intestinal flora, only Clostridium sporogenes was found to produce IPA in culture (Table S2). Based on these results, individual GF mice were intentionally colonized with C. sporogenes strain ATCC 15579, and blood samples were taken at several intervals after colonization. IPA was undetectable in the samples taken shortly after introduction of the microbes, and was first observed in the serum 5 days after colonization, reaching plateau values comparable with conv mice by day 10. These colonization studies demonstrate that the introduction of enteric bacteria capable of IPA production in vivo into the gastrointestinal tract is sufficient to introduce IPA into the bloodstream of the host. Also, other GF animals were injected i.p. with either IPA (at 10, 20, or 40 mg/kg) or sterile PBS vehicle, and their serum concentrations of IPA were measured over time. As seen in Table S3, the high serum levels of IPA observed 1 h after injection decreased more than 90% within 5 h, showing that IPA is rapidly cleared from the blood, and that its presence in the serum of conv animals must result from continuous production from 1 or more bacterial species associated with the mammalian gut.
    IPA 대사 다이어그램
  5. ^ a b c d e f g h i j k l Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
    표 2: 미생물 대사물: 그 합성, 작용 메커니즘, 건강과 질병에 미치는 영향
    그림 1: 숙주 생리와 질병에 대한 인도레와 그 대사물의 분자 작용 메커니즘
  6. ^ a b Attwood G, Li D, Pacheco D, Tavendale M (June 2006). "Production of indolic compounds by rumen bacteria isolated from grazing ruminants". Journal of Applied Microbiology. 100 (6): 1261–71. doi:10.1111/j.1365-2672.2006.02896.x. PMID 16696673. S2CID 35673610.
  7. ^ a b c d e Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999). "Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid". J. Biol. Chem. 274 (31): 21937–21942. doi:10.1074/jbc.274.31.21937. PMID 10419516. S2CID 6630247. [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
  8. ^ Reiter RJ, Guerrero JM, Garcia JJ, Acuña-Castroviejo D (November 1998). "Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin". Annals of the New York Academy of Sciences. 854 (1): 410–24. Bibcode:1998NYASA.854..410R. doi:10.1111/j.1749-6632.1998.tb09920.x. PMID 9928448. S2CID 29333394.
  9. ^ de Mello VD, Paananen J, Lindström J, Lankinen MA, Shi L, Kuusisto J, et al. (April 2017). "Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study". Scientific Reports. 7: 46337. Bibcode:2017NatSR...746337D. doi:10.1038/srep46337. PMC 5387722. PMID 28397877.
  10. ^ Tuomainen M, Lindström J, Lehtonen M, Auriola S, Pihlajamäki J, Peltonen M, et al. (May 2018). "Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals". Nutrition & Diabetes. 8 (1): 35. doi:10.1038/s41387-018-0046-9. PMC 5968030. PMID 29795366.
  11. ^ Keszthelyi D, Troost FJ, Masclee AA (December 2009). "Understanding the role of tryptophan and serotonin metabolism in gastrointestinal function". Neurogastroenterology and Motility. 21 (12): 1239–49. doi:10.1111/j.1365-2982.2009.01370.x. PMID 19650771. S2CID 23568813. Indolylpropionic acid can be further converted in the liver or kidney into indolyl acrylic acid (IAcrA) and conjugated with glycine to produce indolylacryloyl glycine (IAcrGly). ... Also, indolyl propionic acid has been shown to be a powerful antioxidant, and is currently being investigated as a possible treatment for Alzheimers disease.40
  12. ^ Poeggeler B, Sambamurti K, Siedlak SL, Perry G, Smith MA, Pappolla MA (April 2010). "A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan". PLOS ONE. 5 (4): e10206. Bibcode:2010PLoSO...510206P. doi:10.1371/journal.pone.0010206. PMC 2858081. PMID 20421998.
  13. ^ Karbownik M, Reiter RJ, Garcia JJ, Cabrera J, Burkhardt S, Osuna C, Lewiński A (2001). "Indole-3-propionic acid, a melatonin-related molecule, protects hepatic microsomal membranes from iron-induced oxidative damage: relevance to cancer reduction". Journal of Cellular Biochemistry. 81 (3): 507–13. doi:10.1002/1097-4644(20010601)81:3<507::AID-JCB1064>3.0.CO;2-M. PMID 11255233.
  14. ^ Reiter RJ, Tan DX, Osuna C, Gitto E (2000). "Actions of melatonin in the reduction of oxidative stress. A review". Journal of Biomedical Science. 7 (6): 444–58. doi:10.1007/bf02253360. PMID 11060493.