Isoleucine absence from adult human hemoglobin is mirrored in mosquito proteomes and limits malaria parasite growth.

Amino acid composition within a proteome is conventionally viewed as a property of individual protein function. However, specific nutrient scarcity has been shown to reshape which amino acids are encoded in the genome of microbes. Mosquitoes have fed on blood for 200 million years, relying on blood amino acids for reproduction. We wondered whether this ancient dependency has left an imprint on the mosquito proteome. Here we show a proteome-wide shift to lower isoleucine usage in blood-feeding mosquitoes, mirroring the known isoleucine deficiency of adult human hemoglobin. In comparing amino acid composition across the proteomes of blood-feeding and non-blood-feeding mosquitoes, we found that blood feeders show systematically lower isoleucine usage and that highly expressed gut enzymes that digest the blood meal are nearly isoleucine free. Analysis of 707 vertebrate genomes reveals that isoleucine deficiency in major hemoglobin subunits is shared among mammals. Specifically, all non-Malagasy primates, including humans, lack isoleucine in their adult hemoglobin subunits while retaining it in fetal and embryonic subunits. We find that two other major blood proteins, serum albumin and immunoglobulin G, also have reduced isoleucine levels (~1.4%) compared to the human proteome-wide average of 4.38%. Finally, we reasoned that this widespread isoleucine restriction could serve to defend adult red blood cells against isoleucine-dependent blood parasites that feed on them. We tested this hypothesis with the malaria parasite