#BlackInChem Day 2: Although I am an analytical chemist at heart, over the years, I've drifted so much into biology that I am now building a career as a malariologist😅.
For #BlackInBiological, let me tell you about PfcPRS, the protein that was at the center of my PhD research.
The image above is a representation of the structure of the human version of the protein (this will be important later 😀). It was solved by the Schimmel group at @scrippsresearch using X-ray diffraction (analytical chem, FTW!). nature.com/articles/natur… (ncbi.nlm.nih.gov/pmc/articles/P…)
So what is PfcPRS? It is the (c)ytoplasmic (p)rolyl t(R)NA (s)ynthetase in (P)lasmodium (f)alciparum, the deadliest malaria parasite.
It catalyzes the formation of proline building blocks for protein synthesis.
During his PhD, Jon Herman (@hermanjd) identified PfcPRS as the target of a natural product febrifugine and it's synthetic derivative, halofuginone (I will tell you the story of HFG some other time) stm.sciencemag.org/content/7/288/… pubmed.ncbi.nlm.nih.gov/25995223
PfcPRS is not the only prolyl tRNA synthetase in P. falciparum! In fact, the (c) specifies that it located in the cytoplasm. There is also an aPRS, which is found in the (a)picoplast. The cytoplasm is the green background that the other organelles are suspended in.
cPRS and aPRS are part of a family of enzymes called amino acyl tRNA synthetases (aaRS) that are essential in ALL forms of life! Each of the 20 amino acids that make up all the proteins in our bodies are activated by a member of this enzyme family.
Protein synthesis is such a crucial function that aaRSes in different organisms are quite similar. Only a few amino acids (highlighted in blue) differentiate the human PRS from PfcPRS. This picture also shows how halofuginone (HFG) binds to PfcPRS by displacing proline & tRNA.
The experiments that identified cPRS as the target of HFG revealed a different and independent mode of drug resistance. I spent the last 5 years working out the mechanism of this Adaptive Proline Response (APR). Stay tuned for the paper. #BlackInChem /END genomebiology.biomedcentral.com/articles/10.11…
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