Betulinic acid

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. It is found in the bark of several species of plants, principally the white birch (Betula pubescens) from which it gets its name, but also the ber tree (Ziziphus mauritiana), selfheal (Prunella vulgaris), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas, a member of the persimmon family, Tetracera boiviniana, the jambul (Syzygium formosanum), flowering quince (Pseudocydonia sinensis, former Chaenomeles sinensis KOEHNE),
rosemary,
and Pulsatilla chinensis.

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. Then it was demonstrated to induce apoptosis in human neuroblastoma in vitro and in vivo in model systems. At one time, it was undergoing drug development with assistance from the Rapid Access to Intervention Development program of the National Cancer Institute.) and malignant brain tumors, ovarian carcinoma,
In contrast, epithelial tumors, such as breast, colon, small cell lung and renal cell carcinomas, as well as T cell leukemia cells, were completely unresponsive to treatment with betulinic acid.

Regarding the mode of action of betulinic acid, little is known about its antiproliferative and apoptosis inducing mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is accompanied by caspase activation, mitochondrial membrane alterations and DNA fragmentation. Alternatively, Rieber suggested betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53. The study also demonstrated preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma cells, with greater DNA fragmentation and growth arrest and earlier loss of viability than their nonmetastatic C8161/neo 6.3 counterpart. A study of a combination of betulinic acid with γ irradiation showed clearly additive effects, and indicated they differ in their modes of action.

There has been great emphasis on the use of betulinic acid as an antioxidative additive. Creams containing betulinic acid have been proven to help against highly reactive radicals that might cause skin DNA damage. Furthermore, betulinic acid was able to counteract the effects of ionizing radiation like UV. This makes betulinic acid a great additive for sunscreems and sunblocks and also creams for anti aging purposes.

Saccharomyces cerevisiae has been engineered to produce betulinic acid from the mevalonate pathway, with squalene 2,3 epoxide as an intermediate. Acetyl CoA is converted to squalene through use of the 3 hydroxyl 3 methylglutaryl CoA reductase (HMGR) and the bifunctional farnesyl diphosphate farnesyltransferase and squalene synthase (ERG9) and oxidation of NADPH to NADP+. This is then further oxygenated by the squalene monooxygenase (ERG1) to squalene 2,3 epoxide. This is cyclized to lupeol by the Arabidopsis thaliana lupeol synthase (AtLUP1). Finally, lupeol is converted to betulinic acid through the Catharanthus roseus P450 monooxygenase (CrAO) with the oxidation of NADPH to NADP+. [[File:Betulinic Acid Biosynthesis. png|thumb|Biosynthetic pathway of betulinic acid, with all of the enzymes, structures, and cofactors as described by Li et al. in "Modulating betulinic acid production in Saccharomyces cerevisiae by managing the intracellular supplies of the co factor NADPH and oxygen".