Need help optimizing mysql on a busy server
If you have frequent updates, then you should be using InnoDB as with MyISAM the whole table gets locked.

If you have so much RAM, you could set up large buffers to keep your tables completely in memory, which should give you a big improvement in performance.

Try turning on the slow query log to capture slow queries and queries not using indexes. You could use Percona's pt-query-digest tool to analyze the slow query log. Try tuning the slowest queries first and adding any indexes if necessary.