GTP

The energy available from GTP hydrolysis is the same as ATP hydrolysis, but GTP is utilized for different purposes than ATP due to the selectivity of specific enzymes.

GTP concentrations in cells are on average tenfold lower than the millimolar ATP.

GTP is a major regulator of multiple energy-dependent cellular processes of protein synthesis and vesicular trafficking involving endocytosis and autophagy. (R2)

Inhibition of IMP to GMP conversion depletes GTP

the roles of GTP and GTP-binding proteins in the physiology of the normal pancreatic β-cell have been studied in our laboratory using specific inhibitors of inosine monophosphate dehydrogenase, e.g. mycophenolic acid (MPA) and mizoribine (MZ), as tools (3–8). These agents deplete cellular GTP by blockade of the conversion of IMP to GMP, the precursor to the synthesis of GDP and GTP. (R1)

Insulin secretion is inhibited by depletion of GTP

short term (18-h) exposure to MPA or MZ inhibited the production of guanine nucleotides and, concomitantly, potently inhibited nutrient-induced insulin secretion in isolated islets.

Subsequently, we also observed that depletion of GTP using MPA or MZ inhibited Ca2+-stimulated insulin secretion from cloned β-cells (HIT-T15 and INS-1) (9).

The effects of MPA or MZ were specific for the depletion of guanine nucleotides, as their effects were totally reversed by provision of guanine or guanosine, but not by adenine or adenosine (R1)

Depletion of GTP possibly blocks mitogenesis

We found that 1–4 days of treatment of β-cells with GTP-depleting agents blocked mitogenesis, followed by progressive cell killing in a manner of cell death characteristic of apoptosis (programed cell death) (R1)

Free GTP level can be increased by boosting NAD level

As detailed in Section 10, pretreatment of these neurons with an NAD+-precursor, nicotinamide, raised the free GTP levels (R2)

Bound GTP is localized in vesicles

we examined the bound GTP that appears to be localized in vesicles, and increased by nicotinamide (R2)

High consumption of GTP in tissues that actively make proteins

GTP is particularly important for protein synthesis where two GTP molecules are consumed per every one amino acid incorporation into a polypeptide.

Therefore, a large amount of GTP is required in rapidly dividing cells, such as tumor cells, and tissues producing serum proteins, such as the liver, pancreas, and adipose tissue (R3)

PI5P4Kb is a metabolic GTP sensor

Here we report that PI5P4Kb, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kb preferentially utilizes GTP, rather than ATP, for PI(5) P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kb is critical for metabolic adaptation and tumorigenesis.

These results demonstrate that PI5P4Kb is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kb. (R3)

Gene: PIP4K2B (Uniprot)

Succinate-CoA ligase (GDP-forming)

The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and specificity for either ATP or GTP is provided by different beta subunits.

Subunit alpha: SUCLG1 Subunit beta (GTP forming): SUCLG2 (binds 1 magnesium per subunit) Subunit beta (ATP forming): SUCLA2 (binds 1 magnesium per subunit)