5-Hydroxyindoleacetaldehyde

{{Short description|Inactive metabolite of the neurotransmitter serotonin}}

{{Chembox

| ImageFile = 5-Hydroxyindolacetaldehyd.svg

| ImageSize = 200px

| IUPACName = 2-(5-hydroxy-1H-indol-3-yl)acetaldehyde

| OtherNames = 5-Hydroxyindole-acetaldehyde; 5-HIAL; 5-HIAAL; 5-Hydroxytryptaldehyde; 5-Hydroxyindole-3-acetaldehyde; Serotonin aldehyde

| Section1 = {{Chembox Identifiers

| CASNo = 1892-21-3

| CASNo_Ref = {{Cascite|correct|CAS}}

| ChEBI = 50157

| ChEMBL =

| ChemSpiderID = 67261

| DrugBank =

| EINECS =

| IUPHAR_ligand = 6634

| InChI = 1S/C10H9NO2/c12-4-3-7-6-11-10-2-1-8(13)5-9(7)10/h1-2,4-6,11,13H,3H2

| InChIKey = OBFAPCIUSYHFIE-UHFFFAOYSA-N

| KEGG = C05634

| MeSHName =

| PubChem = 74688

| SMILES = C1=CC2=C(C=C1O)C(=CN2)CC=O

| UNII = DAE26MT2UK

}}

| Section2 = {{Chembox Properties

| C=10 | H=9 | N=1 | O=2

| MolarMass = 175.18 g/mol

| Appearance =

| Density =

| MeltingPt =

| BoilingPt =

| Solubility =

}}

| Section3 = {{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

}}

5-Hydroxyindoleacetaldehyde (5-HIAL), also known as 5-hydroxytryptaldehyde or as serotonin aldehyde, is an inactive metabolite and metabolic intermediate of the monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT).{{cite book | last1=Bortolato | first1=Marco | last2=Chen | first2=Kevin | last3=Shih | first3=Jean C. | title=Handbook of Behavioral Neuroscience | chapter=The Degradation of Serotonin: Role of MAO | publisher=Elsevier | volume=21 | date=2010 | isbn=978-0-12-374634-4 | doi=10.1016/s1569-7339(10)70079-5 | pages=203–218}}{{cite journal | vauthors = Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M | title = Tryptophan hydroxylase as novel target for the treatment of depressive disorders | journal = Pharmacology | volume = 85 | issue = 2 | pages = 95–109 | date = 2010 | pmid = 20130443 | doi = 10.1159/000279322 | url = }}{{cite journal | vauthors = Jinsmaa Y, Cooney A, Sullivan P, Sharabi Y, Goldstein DS | title = The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein | journal = Neurosci Lett | volume = 590 | issue = | pages = 134–137 | date = March 2015 | pmid = 25637699 | pmc = 4755587 | doi = 10.1016/j.neulet.2015.01.064 | url = }}

5-HIAL is formed from serotonin by oxidative deamination via monoamine oxidase (MAO). MAO-mediated deamination is the primary metabolic pathway of serotonin inactivation. Monoamine oxidase A (MAO-A) has about 120-fold higher affinity for serotonin than monoamine oxidase B (MAO-B). In relation to this, MAO-A is the main isozyme of MAO involved in serotonin degradation.

Following its formation, 5-HIAL is metabolized by aldehyde dehydrogenase (ALDH) to form 5-hydroxyindoleacetic acid (5-HIAA). 5-HIAL can also be converted into small amounts of 5-hydroxytryptophol (5-HTOL; also known as 5-hydroxyindolethanol or 5-HIET) by either aldehyde reductase (ALR/ALDR) or alcohol dehydrogenase (ADH).{{cite journal | vauthors = Bortolato M, Shih JC | title = Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence | journal = Int Rev Neurobiol | series = International Review of Neurobiology | volume = 100 | issue = | pages = 13–42 | date = 2011 | pmid = 21971001 | pmc = 3371272 | doi = 10.1016/B978-0-12-386467-3.00002-9 | isbn = 978-0-12-386467-3 | url = }} However, brain concentrations of 5-HTOL are only 1 to 5% of those of 5-HIAA.

Use of ethanol (alcohol) can dramatically increase 5-HTOL formation by inhibiting ALDH and enhancing ADH activity.{{cite journal | vauthors = Beck O, Helander A | title = 5-hydroxytryptophol as a marker for recent alcohol intake | journal = Addiction | volume = 98 Suppl 2 | issue = | pages = 63–72 | date = December 2003 | pmid = 14984243 | doi = 10.1046/j.1359-6357.2003.00583.x | url = }} As a result, the ratio of 5-HTOL to 5-HIAA is a sensitive and reliable marker of recent ethanol ingestion and has been suggested for use in clinical and forensic contexts.

Besides oxidative deamination by MAO into 5-HIAL, serotonin can also be conjugated by glucuronidation via glucuronyltransferases, conjugated by sulfation via sulfotransferases, acetylated and then methylated into melatonin (N-acetyl-5-methoxytryptamine) (which occurs mainly in the pineal gland), and converted into certain other metabolites like 5-hydroxyindole thiazoladine carboxylic acid (5-HITCA). However, these secondary metabolic pathways appear to play only a minor role in serotonin metabolism.

5-HIAL has been implicated in producing neurotoxicity and in the development and progression of neurodegenerative diseases.{{cite journal | vauthors = Cagle BS, Crawford RA, Doorn JA | title = Biogenic Aldehyde-Mediated Mechanisms of Toxicity in Neurodegenerative Disease | journal = Curr Opin Toxicol | volume = 13 | issue = | pages = 16–21 | date = February 2019 | pmid = 31304429 | pmc = 6625780 | doi = 10.1016/j.cotox.2018.12.002 | bibcode = 2019COTox..13...16C | url = }}{{cite journal | vauthors = Matveychuk D, MacKenzie EM, Kumpula D, Song MS, Holt A, Kar S, Todd KG, Wood PL, Baker GB | title = Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine | journal = Cell Mol Neurobiol | volume = 42 | issue = 1 | pages = 225–242 | date = January 2022 | pmid = 33839994 | pmc = 8732914 | doi = 10.1007/s10571-021-01078-3 | url = }}{{cite journal | vauthors = Behl T, Kaur D, Sehgal A, Singh S, Sharma N, Zengin G, Andronie-Cioara FL, Toma MM, Bungau S, Bumbu AG | title = Role of Monoamine Oxidase Activity in Alzheimer's Disease: An Insight into the Therapeutic Potential of Inhibitors | journal = Molecules | volume = 26 | issue = 12 | date = June 2021 | page = 3724 | pmid = 34207264 | pmc = 8234097 | doi = 10.3390/molecules26123724 | doi-access = free | url = }}