DHSA

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DHSA
DHSA.svg
Names
IUPAC name
3,4-Dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione
Systematic IUPAC name
(3aS,4S,7aS)-4-[2-(2,3-Dihydroxy-6-methylphenyl)ethyl]-7a-methylhexahydro-1H-indene-1,5(4H)-dione
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
DrugBank
KEGG
PubChem CID
  • InChI=1S/C19H24O4/c1-11-3-7-16(21)18(23)12(11)4-5-13-14-6-8-17(22)19(14,2)10-9-15(13)20/h3,7,13-14,21,23H,4-6,8-10H2,1-2H3/t13-,14-,19-/m0/s1 Yes check.svgY
    Key: YUHVBHDSVLKFNI-NJSLBKSFSA-N Yes check.svgY
  • CC1=C(C(=C(C=C1)O)O)CCC2C3CCC(=O)C3(CCC2=O)C
Properties
C19H24O4
Molar mass 316.39146
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

3,4-DHSA is an organic compound which is the intermediate product of the metabolism of cholesterol, by the bacteria most commonly responsible for tuberculosis ( Mycobacterium tuberculosis ). [1] 3,4-DHSA is an acronym for 3,4-dihydroxy-9,10-seco-androst-1,3,5(10)-triene-9,17-dione, the official name of this substance. It is classified as a secosteroid, since one of the four rings of cholesterol from which it is derived is broken.

3,4-DHSA is a catecholic intermediate (a compound containing an aromatic ring with two adjacent hydroxyl groups) produced by M. tuberculosis during the breakdown of cholesterol. [1] 3,4-DHSA is also produced by other bacteria such as Comamonas testosteroni . [2] [3]

A particular type of enzyme known as extradiol dioxygenase is responsible for the oxidation and ring opening of 3,4-DHSA to 4,9-DSHA (see metabolic scheme below). M. tuberculosis bacteria that are deficient in this enzyme are less lethal than wild-type bacteria. 3,4-DHSA itself appears to be toxic to the bacteria while the breakdown products of 3,4-DHSA can be used as energy source by the bacteria. Hence blocking the oxidation of 3,4-DHSA by the extradiol dioxygenase enzyme may be useful in the treatment of tuberculosis. [1]

A crystal structure of DHSA in complex with M. tuberculosis iron-dependent extradiol dioxygenase has been determined. [1]

Synthesis and degradation of 3,4-DHSA. DHSA metabolism.tif
Synthesis and degradation of 3,4-DHSA.

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4,5:9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate hydrolase (EC 3.7.1.17, tesD (gene), hsaD (gene)) is an enzyme with systematic name 4,5:9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate hydrolase ( (2Z,4Z)-2-hydroxyhexa-2,4-dienoate-forming). This enzyme catalyses the following chemical reaction

2-hydroxyhexa-2,4-dienoate hydratase (EC 4.2.1.132, tesE (gene), hsaE (gene)) is an enzyme with systematic name 4-hydroxy-2-oxohexanoate hydro-lyase ((2Z,4Z)-2-hydroxyhexa-2,4-dienoate-forming). This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 4 5 PDB: 2ZI8 ​; Yam KC, D'Angelo I, Kalscheuer R, Zhu H, Wang JX, Snieckus V, Ly LH, Converse PJ, Jacobs WR, Strynadka N, Eltis LD (March 2009). Ramakrishnan L (ed.). "Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis". PLOS Pathog. 5 (3): e1000344. doi: 10.1371/journal.ppat.1000344 . PMC   2652662 . PMID   19300498.
  2. ↑ Horinouchi M, Kurita T, Yamamoto T, Hatori E, Hayashi T, Kudo T (November 2004). "Steroid degradation gene cluster of Comamonas testosteroni consisting of 18 putative genes from meta-cleavage enzyme gene tesB to regulator gene tesR". Biochem. Biophys. Res. Commun. 324 (2): 597–604. doi:10.1016/j.bbrc.2004.09.096. PMID   15474469.
  3. ↑ Horinouchi M, Hayashi T, Kudo T (October 2004). "The genes encoding the hydroxylase of 3-hydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione in steroid degradation in Comamonas testosteroni TA441". J. Steroid Biochem. Mol. Biol. 92 (3): 143–54. doi:10.1016/j.jsbmb.2004.09.002. PMID   15555908. S2CID   24549812.
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