Metabolomics Reveals Differential Levels of Oral Metabolites in HIV-Infected Patients: Toward Novel Diagnostic Targets

The objective of the current study was to characterize the profile of oral metabolites in HIV-infected patients using metabolomics. Oral wash samples were collected from 12 HIV-infected and 12 healthy individuals (matched for age, sex, and ethnicity), processed, and analyzed by metabolomics. We detected 198 identifiable and 85 nonidentifiable metabolites; 27 identifiable metabolites were differentially present (12 increased, 15 decreased) in HIV-infected patients. Elevated metabolites included p-cresol sulfate, nucleotides (e.g., allantoin), and amino acids (e.g., phenylalanine, tryptophan), whereas decreased oral metabolites included fucose, fumarate, and N-acetylglucosamine. Pathway network analysis revealed the largest multinode network in healthy versus HIV-infected patients to involve carbohydrate biosynthesis and degradation. HIV-infected patients on antiretroviral therapy (ART) showed the largest number (12) of statistically significant metabolite correlation differences compared with healthy controls. Interestingly, the oral phenlyalanine:tyrosine ratio increased in ART-naive HIV-infected patients (mean ± SEM = 2.58 ± 0.87) compared with healthy individuals (1.33 ± 0.10, p = 0.062) or ART-experienced patients (1.78 ± 0.30, p = 0.441). This is the first study to reveal differential levels of oral metabolites in HIV-infected patients compared withj healthy volunteers, and that oral phenlyalanine:tyrosine ratio may be a useful marker for noninvasive monitoring of the immune status during HIV infection

Secondary metabolic gene cluster silencing in Aspergillus nidulans

In contrast to most primary metabolism genes, the genes involved in secondary metabolism and certain nutrient utilization pathways are clustered in fungi. Recently a nuclear protein, LaeA, was found to be required for the transcription of several secondary metabolite gene clusters in Aspergillus nidulans. Here we show that LaeA regulation does not extend to nutrient utilization or the spoC1 sporulation clusters. One of the secondary metabolite clusters regulated by LaeA contains the positive regulatory (i.e. aflR) and biosynthetic genes required for biosynthesis of sterigmatocystin (ST), a carcinogenic toxin. Analysis of ST gene cluster expression indicates LaeA regulation of the cluster is location specific as transcription of genes bordering the ST cluster are unaffected in a ΔlaeA mutant and placement of a primary metabolic gene, argB, in the ST cluster resulted in argB silencing in the ΔlaeA background. ST cluster gene expression was remediated when an additional copy of aflR was placed outside of the cluster but not when placed in the cluster. Site-specific mutation of an s-adenosyl methionine (AdoMet) binding site in LaeA generated a ΔlaeA phenotype suggesting the protein to be a methyltransferase