KCS1 encodes one of two yeast inositol pyrophosphate synthases (also known as inositol hexakisphophate kinases; IP6Ks); the other is encoded by VIP1. The inositol pyrophosphates (PP-IPs) produced by Kcs1p and/or Vip1p serve as high-energy signaling molecules involved in such diverse processes as vacuolar biogenesis, the stress response, DNA repair, cell wall synthesis, telomere maintenance, and phosphate homeostasis (see 5, 6, 7, and references therein).

Both enzymes catalyze the addition of beta-phosphate to the fully phosphorylated six-carbon ring of inositol hexakisphosphate (IP6). However, these enzymes produce different isomers of diphosphoinositol pentakisphosphate (IP7). Kcs1p phosphorylates IP6 at the C5 position forming 5PP-IP5, and Vip1p phosphorylates IP6 at the C4 or C6 position forming 4PP-IP5 or 6PP-IP5, respectively (the exact phosphorylation position has not yet been determined). The different IP7 isomers are biologically relevant: the Kcs1p product cannot substitute for the Vip1p product during phosphate homeostasis (8). Kcs1p and Vip1p also work in concert to produce bis-diphosphoinositol tetrakisphosphate ([PP]2-IP4; IP8). Kcs1p phosphorylates the Vip1p IP7 product 4/6PP-IP5, and Vip1p phosphorylates the Kcs1p IP7 product 5PP-IP5 (4).

Although Kcs1p function has been best characterized on the IP6 and IP7 substrates, this enzyme has also been demonstrated to possess kinase activity on a number of other inositol phosphates substrates that do not have a full complement of alpha-phosphorylation, including I(1,4,5)P3 (3), I(1,3,4,5)P4 (3), I(1,3,4,5,6,)P5 (2), and PP-IP4 (2). The physiological relevance of these reactions is unclear at this time.

Inositol pyrophosphate synthases are highly conserved and found across eukaryotes. In humans, three Kcs1p-like enzymes (IHPK1/IP6K1, IP6K2/IP6K2, IP6K3/IP6K3) (9, 10) and two Vip1p-like enzymes (HISPPD2a/PPIP5K1/VIP1 and PPIP5K2/VIP2) (11, 12) have been identified.

Last updated: 2008-01-22