The Pythagorean comma is nothing to worry about -- it's tiny and more or less negligible. It's the syntonic comma that's the killer.
The fifths in equal temperament are completely fine, but the thirds are really quite a ways off from the harmonic 5/4 major third. I would recommend experimenting with the traditional meantone tuning system if you're interested in this -- it offers almost as much flexibility as equal temperament (with 6 adjacent keys on the circle of fifths being free of wolf intervals), and it lets you play with "real thirds".
The fifths in equal temperament are completely fine, but the thirds are really quite a ways off from the harmonic 5/4 major third. I would recommend experimenting with the traditional meantone tuning system if you're interested in this -- it offers almost as much flexibility as equal temperament (with 6 adjacent keys on the circle of fifths being free of wolf intervals), and it lets you play with "real thirds".