Bioactive lipids such as ceramides, sphingosines and their analogs play an important role in cell growth, senescence and apoptosis. The manipulation of these cell functions can halt cancer cell growth which can be applied to therapeutics. Nonetheless, organic synthesis of these bioactive lipids is complex and laborious resulting in exorbitant production costs. 5-aminolevulinate synthase (ALAS) (EC 2.3.1.37) is a pyridoxal phosphate (PLP)-dependent enzyme that produces 5-aminolevulinate and CO2 from glycine and succinyl-CoA. Modification of this enzyme to accept other substrates such as L-serine and different types of acyl-CoA can allow us to synthesize 3-keto-dihydrosphingosine analogs which then can be used as building blocks for bioactive lipids. Studies show that mutation of ALAS on T83, a glycine binding-threonine, to a smaller amino acid allows it to accept larger substrates than glycine which includes L-serine. Furthermore, R85, which is an arginine that interacts with carboxylate component of succinyl-CoA, shows increased activity toward butyryl-CoA and octanoyl-CoA than the wild-type when replaced with lysine. These results show the possibility of biochemical synthesis of the bioactive lipids. Although substrate range of ALAS from Rhodobacter spheroids and mus musculus has been widely explored, that of Rhodopseudomonas palustris has not yet been throughly studied. ALAS from R. palustris is easily expressed and purifiable and shows higher activity than the others. Thus, if these mutations can also be applied to R. palustris 5-ALAS, we could be able to synthesize the bioactive lipids in a greener and less expensive way with controlled enantioselectivity.

Synthesizing building blocks for bioactive lipids: Biocatalytic approach using 5-aminolevulinic acid synthase

2019 Spring National Meeting

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