Characterization of Quinolinic Acid Phosphoribosyltransferase in Human Blood and Observations in Huntington's Disease

Abstract

Quinolinic acid (QUIN), an excitotoxic compound present in the mammalian CNS and periphery, was hypothetically linked to human neurodegenerative disorders such as Huntington''s disease and epilepsy. Quinolinic acid phosphoribosyltransferase (QPRT), the catabolic enzyme of QUIN, is found in the CNS and peripheral organs where it may be a major influence on the tissue levels of QUIN. QPRT activity in human blood as a means of assessing 1 aspect of QUIN metabolism in humans was measured. The enzyme was present in blood cells, platelets having a 6-fold greater activity than erythrocytes, but was essentially absent from the plasma. In a blood cell fraction, enzyme activity was potently inhibited by phthalic acid (IC50 = 6.1 .mu.M). Kinetic analyses conducted over a range of QUIN concentrations yielded Km values of 1.89-3.75 .mu.M and Vmax values of 33.4-72.5 fmol nicotinic acid mononucleotide h/mg protein. Enzyme activity varied 2.2-fold between normal individuals, was reasonably constant over a series of sampling intervals and showed some diminution when blood was stored for 1 mo. at -20.degree. C. No differences of enzyme activity in erythrocytes or platelets were apparent between 3 Huntington''s disease patients and their unaffected spouses. Apparently measurements of QPRT activities in blood are a convenient means to monitor QUIN metabolism in human subjects and that a deficiency of the enzyme is not apparent in Huntington''s disease.