Is phylogenetic distance between worms and humans negated in some cases? If a certain gene function is conserved throughout such organisms, our naïve question would be how often the gene itself can be intactly replaceable between them beyond some 990 million years. As a group, teleost fish are phylogenetically well positioned for comparisons to other vertebrates, having diverged from the amniote lineage (mammals, birds, reptiles) some 400 million years ago. The comparison with human genomes also provides an opportunity to examine the dynamics of fish chromosomal evolution. The genomes of zebrafish (Danio rerio) species have been sequenced with annotations and display remarkable structural similarity with the human genome, meaning that findings from zebrafish provide insights into many human conditions and diseases. While many molecules have been considered for their functional conservation among invertebrate and vertebrate species, as far as we know, little has been demonstrated for truly reciprocal compatibility between them. Here, for the first time, utilizing the zebrafish model system, we show that the putative lysosomal sympoter Spinster (Spin)/Spinster homolog 1 (Spns1) is evolutionarily conserved and replaceable across wide variety species from worms through humans beyond approximately one-billion years’ evolutionary distance. We demonstrate that human Spns1, Drosophila Spin and C. elegans Spin-1 are functionally compatible to zebrafish Spns1 and transgenic expressions of any of these Spin/Spns1 can rescue zebrafish spns1 mutants with successful generations of the stable transgenic lines. Homology-scanning mutagenesis of Spin/Spns1 further confirmed the biologically functional and potential ligand-binding capabilities of the proteins in vivo and in vitro, respectively. We further demonstrate that a sugar-derived molecule, rather than a conventional sugar, is a common ligand for both human and zebrafish Spns1. Finally, primary and tertiary structure analysis reveal that the Spin/Spns1 proteins have unique substrate- and proton-binding sites as symporters, suggesting that these proteins may represent a novel, as yet unclassified, type of the solute carrier family.