The discovery of tRNA originated from studies on protein synthesis in the 1950s. In 1956, Paul Zamecnik and Mahlon Hoagland were investigating how amino acids are assembled into proteins. They identified an enzyme, later called the pH 5 enzyme, that activated amino acids using ATP, producing aminoacyl-adenylates, an essential step in protein synthesis.
In 1957, Hoagland, Ogata, and Nohara discovered that this enzyme also transferred amino acids onto an unknown RNA molecule. Further experiments confirmed that this RNA was an essential carrier of amino acids in protein formation. Zamecnik and his colleagues initially named it soluble RNA (sRNA), but it was later renamed transfer RNA (tRNA) as its function became clearer.
The connection between tRNA and protein synthesis was further established when, in 1958, Berg, Ofengand, and Lipmann discovered aminoacyl-tRNA synthetases, enzymes that specifically attach amino acids to their corresponding tRNA molecules. This process ensures the accurate delivery of amino acids during protein formation.
In the same year (1958), Hans Zachau in Lipmann’s lab found that amino acids attach to the 3′-end (CCA sequence) of tRNA. Meanwhile, Francis Crick had proposed the Adaptor Hypothesis (1955–1958), suggesting that a molecule must exist to link amino acids to genetic instructions. The discovery of tRNA confirmed Crick’s idea, proving that tRNA acts as an adaptor that translates genetic code into proteins.
By the 1960s, scientists like Robert Holley began sequencing tRNA, leading to the complete sequence of tRNAAla (alanine tRNA) in 1965. This milestone provided deeper insight into how tRNA functions in protein synthesis.
Thus, research on protein synthesis (1950s–1960s) led to the discovery of tRNA, revealing its essential role in delivering amino acids to ribosomes and ensuring the accurate translation of genetic information into proteins. These discoveries laid the foundation for decoding the genetic code, marking a major milestone in molecular biology.
Ref: RajBhandary, Uttam L., and Caroline Köhrer. “Early days of tRNA research: discovery, function, purification and sequence analysis.” Journal of biosciences 31.4 (2006): 439-451.