iodoacetic acid

Iodoacetate is an irreversible inhibitor of all cysteine peptidases, with the mechanism of inhibition occurring from alkylation of the catalytic cysteine residue (see schematic). In comparison with its amide derivative, iodoacetamide, iodoacetate reacts substantially slower. This observation appears contradictory to standard chemical reactivity, however the presence of a favourable interaction between the positive imidazolium ion of the catalytic histidine and the negatively charged carboxyl-group of the iodoacetic acid is the reason for the increased activity of iodoacetamide.{{cite journal | author = Polgár, L. | title = Deuterium isotope effects on papain acylation. Evidence for lack of general base catalysis and for enzyme-leaving group interaction | journal = European Journal of Biochemistry | year = 1979 | volume = 98 | issue = 2 | pages = 369–374 | doi = 10.1111/j.1432-1033.1979.tb13196.x | pmid = 488108 | doi-access = free}}Image:Iodoacetic acid mechanism.svgs with iodoacetate.]]{{clear left}}

Several studies have shown iodoacetate has anti-tumor effects. In 2002 Fawzia Fahim showed that "a single IAA treatment of tumor-bearing mice significantly increased the levels of plasma lactate dehydrogenase (LDH) activity, while it also significantly decreased the levels of plasma glucose and liver total protein, RNA and DNA, compared to normal controls."{{cite journal |author1=Fahim, F. A. |author2=Esmat, A. Y. |author3=Mady, E. A. |author4=Ibrahim, E. K. | title = Antitumor Activities of Iodoacetate and Dimethylsulphoxide Against Solid Ehrlich Carcinoma Growth in Mice | journal = Biological Research | year = 2003 | volume = 36 | issue = 2 | pages = 253–262 | pmid = 14513720 | doi = 10.4067/S0716-97602003000200015 | doi-access = free}} In 1975 Melvin S. Rhein, Joyce A. Filppi and Victor S. Moore showed that iodoacetate improved the immune response of bone marrow.{{cite journal |author1=Rhein, M. S. |author2=Filppi, J. A. |author3=Moore, V. S. | title = Effect of Iodoacetate on the Bone Marrow Immunocompetence of AKR Mice | journal = Cancer Research | year = 1975 | volume = 35 | issue = 6 | pages = 1514–1519 | pmid = 1093673 | url = http://cancerres.aacrjournals.org/content/35/6/1514.full.pdf}} In 1966 Charles A. Apffel, Barry G. Arnason & John H. Peters showed anti-tumor activity for iodoacetate.{{cite journal |author1=Apffel, C. A. |author2=Arnason, B. G. |author3=Peters, J. H. | title = Induction of tumour immunity with tumour cells treated with iodoacetate | journal = Nature | year = 1966 | volume = 209 | issue = 5021 | pages = 694–696 | pmid = 5922128 | doi = 10.1038/209694a0 | bibcode = 1966Natur.209..694A |s2cid=4296138}}

Iodide is a naturally occurring ion that can be found in many source waters and it is easily oxidized by wastewater disinfectants. One of the products of iodide oxidation is hypoiodous acid or hypoiodite (HOI and {{chem2|OI−}} respectively) which are capable of reacting with background organic materials to generate iodinated disinfection by-products (DBPs) including iodoacetic acid. In a study performed by Plewa, et al., IAA was determined to be one of the most cytotoxic of those studied, with a median lethal dose on the order of magnitude of 10⁻⁵ M. It was the most genotoxic of more than 60 DBPs studied and is the most genotoxic DBP identified thus far.{{cite journal|last1=Plewa|first1=Michael J.|last2=Wagner|first2=Elizabeth D.|last3=Richardson|first3=Susan D.|last4=Thruston|first4=Alfred D. Jr.|last5=Woo|first5=Yin-Tak|last6=McKague|first6=A. Bruce|title=Chemical and Biological Characterization of Newly Discovered Iodoacid Drinking Water Disinfection Byproducts|journal=Environmental Science & Technology|date=2004|volume=38|issue=18|pages=4713–4722|bibcode=2004EnST...38.4713P|doi=10.1021/es049971v|pmid=15487777}} Iodoacetic acid has exhibited traits indicating it as a potential carcinogen, however, it has not been proven to be carcinogenic.{{cite journal |last1=Wei |first1=Xiao |last2=Wang |first2=Shu |last3=Zheng |first3=Weiwei |last4=Wang |first4=Xia |last5=Liu |first5=Xiaolin |last6=Jiang |first6=Songhui |last7=Pi |first7=Jingbo |last8=Zheng |first8=Yuxin |last9=He|first9=Gengsheng|last10=Qu|first10=Weidong|title=Drinking Water Disinfection Byproduct Iodoacetic Acid Induces Tumorigenic Transformation of NIH3T3 Cells|journal=Environmental Science & Technology|date=2013|volume=47|issue=11 |pages=5913–5920 |doi=10.1021/es304786b|pmid=23641915 |bibcode=2013EnST...47.5913W}} The trend continues in teratogenicity, with iodoacetic acid's potency surpassing that of its brominated and chlorinated analogs.{{cite journal|last1=Richard|first1=Ann M.|last2=Hunter|first2=E. Sidney III|title=Quantitative Structure-Activity Relationships for the Developmental Toxicity of Haloacetic Acids in Mammalian Whole Embryo Culture|journal=Teratology|date=1996|volume=53|issue=6|pages=352–360|pmid=8910981|doi=10.1002/(SICI)1096-9926(199606)53:6<352::AID-TERA6>3.0.CO;2-1}} Its toxicity correlates to its ability as an alkylating agent, which will modify cysteine residues in proteins.{{cite web|title=Product #35603|url=http://www.piercenet.com/product/iodoacetic-acid|website=Thermo Scientific. Pierce Protein Biology Products.}} Monohaloacetic acids are the most toxic, with toxicity increasing with halogen size. Iodoacetic acid is more toxic than bromoacetic acid and much more toxic than chloroacetic acid.{{cite journal|last1=Richardson|first1=Susan D.|last2=Plewa|first2=Michael J.|last3=Wagner|first3=Elizabeth D.|last4=Shoeny|first4=Rita|last5=DeMarini|first5=David M|title=Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: A review and roadmap for research|journal=Mutation Research|date=2007|volume=636|issue=1–3|pages=178–242|pmid=17980649|doi=10.1016/j.mrrev.2007.09.001}}

{{Reflist|2}}

• {{cite journal |author1=Knap, A. K. |author2=Pratt, R. F. | title = Inactivation of the RTEM-1 cysteine beta-lactamase by iodoacetate. The nature of active-site functional groups and comparisons with the native enzyme | journal = Biochemical Journal | year = 1991 | volume = 273 | issue = 1 | pages = 85–91 |doi=10.1042/bj2730085 | pmid = 1989590 | pmc = 1149883}}
• {{cite journal | author = Dickens, F. | title = Interaction of halogenacetates and SH compounds. The reaction of halogenacetic acids with glutathione and cysteine. The mechanism of iodoacetate poisoning of glyoxalase | journal = Biochemical Journal | year = 1933 | volume = 27 | issue = 4 | pages = 1141–1151 | doi = 10.1042/bj0271141 | pmid = 16745202 | pmc = 1253000}}

• The MEROPS online database for peptidases and their inhibitors: [http://meropstest.sanger.ac.uk/cgi-bin/smi_summary?mid=J00006 Iodoacetate]{{dead link|date=April 2017 |bot=InternetArchiveBot |fix-attempted=yes}}

{{DEFAULTSORT:Iodoacetic Acid}}

Category:Acetic acids

Category:Alkylating agents

Category:Organoiodides