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The erythrocyte nucleotides of 25 children, 1-5 years old, with normal and increased blood leads, were assayed by anion-exchange high-performance liquid chromatography. Red blood cells of the 12 children with blood lead (PbB) below 30 micrograms/dl (20.3 +/- 6 micrograms/dl, mean +/- S.D.) had normal levels of activity of pyrimidine 5'-nucleotidase (P5N) and their erythrocytes were virtually free of pyrimidine nucleotides except for small amounts of UMP and UDP. The purine nucleotides, predominantly ATP and GTP, were present at values similar to adults. In the 13 children with PbB 30-72 micrograms/dl (45.3 +/- 14.3 micrograms/dl), total cytidine phosphates (CMP, CDP, CTP) were significantly (P less than 0.001) increased from trace values to 8.31 +/- 6.21 nmoles/10(10) erythrocytes. The purine nucleotides were unchanged. P5N activity was 143.3 +/- 22.0 units/g hemoglobin in children with PbB less than 30 micrograms/dl and 75.4 +/- 24.2 units (P less than 0.001) in the high lead subjects. There was a logarithmic correlation of erythrocyte cytidine phosphates with PbB (r = 0.89, P less than 0.001) and an inverse correlation of cytidine phosphates with ln P5N activity (r = 0.59, P less than 0.001), of ln P5N with PbB (r = 0.64, P less than 0.001) and of ln P5N with ln erythrocyte zinc protoporphyrin (Protoporphyrin IX) (r = 0.57, P less than 0.001).
The mixed disulfide of methyl mercaptan and L-homocysteine, S-(methylthio)-L-homocysteine (L-SMETH), inhibits the growth of L-1210 leukemia cells in culture at micromolar concentrations. The inhibition is markedly promoted by added cupric ion, but not by ions of other metals, is stereospecific, and is competitive with glutamine. For example, at 10 microM each of L-SMETH and Cu2+, almost complete growth inhibition was observed if cells were grown in 1 mM glutamine, 50% inhibition at 2 mM glutamine, and none at 4 mM glutamine. The inhibition is also completely relieved by cytidine in noncompetitive manner, but not by guanosine or uridine, indicating that the principal damage to the cellular economy resides in the amination of UTP to CTP. This was confirmed by high performance liquid chromatography analysis of cell extracts, which showed a marked decrease in CTP with increases in the levels of UTP, GTP, and ATP. A major swelling of cells leading to lysis accompanies the inhibition and increases in DNA and protein per cell confirms this unbalanced growth. The chemical basis for this biological interaction is presented.
When calf brain membrane preparations containing endogenous dolichyl [32P]monophosphate (Dol-32P), prelabeled enzymatically by [gamma-32P]-CTP, are incubated with unlabeled UDP-glucose, the formation of a mild acid-labile [32P]phosphoglucolipid is observed. The biosynthesis of the [32P]phosphoglucolipid is dependent on the concentration of UDP-glucose added, and no [32P]phosphoglycolipid appeared when UDP-glucose was replaced by ADP-glucose, UDP-xylose, UDP-galactose, UDP-mannose, or UDP-glucuronic acid. The 32P-labeled product formed by the UDP-glucose-dependent reaction is chemically and chromatographically identical to glucosylphosphoryldolichol. Several enzymatic parameters of the glucosylation of the specific pool of Dol-P, synthesized by the CTP-mediated kinase, and the total available pool of Dol-P have been compared by a double-label assay utilizing endogenous, prelabeled Dol-32P and UDP-[3H]glucose as substrates.
The malarial parasite Plasmodium falciparum is dependent on de novo synthesis for its pyrimidine nucleotide requirements. However, the activity of the key enzyme in cytidine nucleotide synthesis, CTP synthetase (EC 6.3.4.2), has not been reported. We present evidence for a CTP synthetase gene in P. falciparum, having isolated a PCR product obtained using 2 primers derived from the CTP synthetase amino acid consensus sequences DPYINVDPG and GICLGMQ. The amplified DNA segment encodes an amino acid sequence with considerable homology to CTP synthetases from several other species including human and yeast.
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The B. subtilis pyrG gene, which encodes CTP synthetase, is located far from the pyrimidine biosynthetic operon on the chromosome and is independently regulated. The pyrG promoter and 5' leader were fused to lacZ and integrated into the chromosomes of several B. subtilis strains having mutations in genes of pyrimidine biosynthesis and salvage. These mutations allowed the intracellular pools of cytidine and uridine nucleotides to be manipulated by the composition of the growth medium. These experiments indicated that pyrG expression is repressed by cytidine nucleotides but is largely independent of uridine nucleotides. The start of pyrG transcription was mapped by primer extension to a position 178 nucleotides upstream of the translation initiation codon. A factor-independent termination hairpin lying between the pyrG promoter and its coding region is essential for regulation of pyrG expression. Primer-extended transcripts were equally abundant in repressed and derepressed cells when the primer bound upstream of the terminator, but they were much less abundant in repressed cells when the primer bound downstream of the terminator. Furthermore, deletion of the terminator from pyrG-lacZ fusions integrated into the chromosome yielded elevated levels of expression that was not repressible by cytidine. We suggest that cytidine repression of pyrG expression is mediated by an antitermination mechanism in which antitermination by a putative trans-acting protein is reduced by elevated levels of cytidine nucleotides. Conservation of sequences and secondary structural elements in the pyrG 5' leaders of several other gram-positive bacteria indicates that their pyrG genes are regulated by a similar mechanism.
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