Desosamine Explained

Desosamine is a 3-(dimethylamino)-3,4,6-trideoxyhexose found in certain macrolide antibiotics (contain a high level of microbial resistance) such as the commonly prescribed erythromycin,[1] [2] azithromycin, clarithroymcin, methymycin, narbomycin, oleandomycin, picromycin and roxithromycin. As the name suggests, these macrolide antibiotics contain a macrolide or lactone ring and they are attached to the ring Desosamine which is crucial for bactericidal activity.[3] The biological action of the desosamine-based macrolide antibiotics is to inhibit the bacterial ribosomal protein synthesis.[4] These antibiotics which contain Desosamine are widely used to cure bacterial-causing infections in human respiratory system, skin, muscle tissues, and urethra.

Discovery

Although desosamine has been found in many macrolide antibiotics, the complete chemical structure of desosamine was not determined until 1962. Nuclear magnetic resonance spectroscopy data was used to establish the complete configuration of desosamine. The hydrogen atoms at the C1,C2,C3, and C5 positions are all found to be axial.[5]

Biosynthesis

Six enzymes are required for Desosamine biosynthesis from TDP-glucose in Streptomyces venezuelae.[6] In addition to the required enzymes, there are eight important open reading frames known as the des regions, they are desI~desVIII, these eight frames are the necessary genes used in Desosamine biosynthesis, among the 8 des regions, the desI gene implements C-4 Deoxygenation by the enzymatic activity of dehydrase. [7]

Degradation

Degradation of several of the aforementioned antibiotics yields the desosamine sugar. It is found in combination with the smaller macrolide rings, always attached at C-3 or C-5 of the aglycone. Alkaline degradation found the sugar to be a D-hexose derivative.[8] Glycosidic cleavage of methomycin produces aglycone methynolide and the basic sugar desosamine, whose structure had been determined by oxidative degradation to crotonaldehyde and by other experiments.[9]

Drug resistance

Macrolide antibiotics that contain Desosamine as an amino sugar in their chemical structures sometimes encounter drug-resistant bacteria. The target-site modification can result in changing chemical structure of the antibiotics, for example, a methylation mutation, which will block the drug from normally functioning.[10]

See also

External links

Notes and References

  1. Rodríguez E, Peirú S, Carney JR, Gramajo H . In vivo characterization of the dTDP-D-desosamine pathway of the megalomicin gene cluster from Micromonospora megalomicea . Microbiology . 152 . Pt 3 . 667–673 . March 2006 . 16514147 . 10.1099/mic.0.28680-0 . free .
  2. Flickinger MC, Perlman D . Microbial degradation of erythromycins A and B . The Journal of Antibiotics . 28 . 4 . 307–11 . April 1975 . 1150530 . 10.7164/antibiotics.28.307 . free .
  3. Burgie ES, Holden HM . Molecular architecture of DesI: a key enzyme in the biosynthesis of desosamine . Biochemistry . 46 . 31 . 8999–9006 . August 2007 . 17630700 . 2528198 . 10.1021/bi700751d .
  4. Vázquez-Laslop N, Mankin AS . How Macrolide Antibiotics Work . Trends in Biochemical Sciences . 43 . 9 . 668–684 . September 2018 . 30054232 . 6108949 . 10.1016/j.tibs.2018.06.011 .
  5. Woo PW, Dion HW, Durham L, Mosher HS . January 1962 . The stereochemistry of desosamine, an nmr analysis . Tetrahedron Letters. en. 3. 17. 735–739. 10.1016/S0040-4039(00)70510-7 .
  6. Burgie ES, Holden HM . Molecular architecture of DesI: a key enzyme in the biosynthesis of desosamine . Biochemistry . 46 . 31 . 8999–9006 . August 2007 . 17630700 . 2528198 . 10.1021/bi700751d .
  7. Borisova SA, Zhao L, Sherman DH, Liu HW . Biosynthesis of desosamine: construction of a new macrolide carrying a genetically designed sugar moiety . Organic Letters . 1 . 1 . 133–6 . July 1999 . 10822548 . 10.1021/ol9906007 .
  8. Bolton CH, Foster AB, Stacey M, Webber JM . 1961 . Carbohydrate components of antibiotics. Part I. Degradation of desosamine by alkali: Its absolute configuration at position 5 . Journal of the Chemical Society . 1961 . 4 . 4831–4836 . 10.1039/JR9610004831.
  9. Berry M . 1963 . The macrolide antibiotics . Quarterly Reviews, Chemical Society . 17 . 4 . 343–361 . 10.1039/QR9631700343.
  10. Klugman KP, Lonks JR . Hidden epidemic of macrolide-resistant pneumococci . en-us . Emerging Infectious Diseases . 11 . 6 . 802–7 . June 2005 . 15963272 . 3367596 . 10.3201/eid1106.050147 .