Plasmodium falciparum has an AT-rich genome with highly biased codon and amino acid usage that is not balanced by the tRNA genes repertoire. To determine whether individual tRNA genes can be differentially expressed to compensate for the tRNA-codon imbalance, we characterized the tRNA profiles of the parasite. While we found that the parasite stably maintained a biased expression of different tRNAs throughout the intraerythrocytic cycle (IDC), the tRNA-codon imbalance remains. Specifically, the requirements for a limited tRNA subset in the codons of a gene negatively correlated with its mRNA level. A detailed analysis revealed that these observations implicate host adaptation during P. falciparum genome evolution, whereby housekeeping genes evolved to minimize dependence on exogenous amino acids, allowing these genes to mitigate the negative effects during acute nutrient deprivation. We found that these host-adapted features can derive a decentralized nutrient-dependent regulatory programme via sensing isoleucine as a proxy for nutrient stress, which causes a reduction in aminoacylated Ile-tRNA level. This, in turn, rapidly reprogrammes the global protein output and transcriptome in a targeted fashion. Our findings provide strong evidence showing that the primary sequences of proteins underlie gene expression programmes, suggesting new perspectives on protein evolution.