RESUMEN
Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant used for the treatment of attention-deficit/hyperactivity disorder (ADHD) dosed once daily. Due to its long-acting properties, LDX remains pharmacologically inactive until an enzymatic process predominantly associated with red blood cells converts it to the active ingredient, d-amphetamine and the amino acid lysine. The efficacy of LDX over placebo has been demonstrated in several studies in adults with moderate to severe ADHD with significant improvements noted in ADHD rating scales, Clinical Global Improvement scores, and assessments of executive function, for all doses of LDX (30-70 mg daily). Lisdexamfetamine dimesylate has demonstrated efficacy at 14 hours post dose in adults and may be used as a long-acting stimulant for managing ADHD symptoms, which may extend late into the day. Lisdexamfetamine dimesylate has demonstrated a safety profile consistent with long-acting stimulants use. Relevant English language articles were identified through computerized searches of MEDLINE (PubMed and EMBASE) from 1995 to 2016 using the following search terms: lisdexamfetamine dimesylate, attention-deficit hyperactivity disorder, NRP104, and Vyvanse.
RESUMEN
Phenolic glycolipids (PGLs) are polyketide synthase-derived glycolipids unique to pathogenic mycobacteria. PGLs are found in several clinically relevant species, including various Mycobacterium tuberculosis strains, Mycobacterium leprae, and several nontuberculous mycobacterial pathogens, such as M. marinum. Multiple lines of investigation implicate PGLs in virulence, thus underscoring the relevance of a deep understanding of PGL biosynthesis. We report mutational and biochemical studies that interrogate the mechanism by which PGL biosynthetic intermediates (p-hydroxyphenylalkanoates) synthesized by the iterative polyketide synthase Pks15/1 are transferred to the noniterative polyketide synthase PpsA for acyl chain extension in M. marinum. Our findings support a model in which the transfer of the intermediates is dependent on a p-hydroxyphenylalkanoyl-AMP ligase (FadD29) acting as an intermediary between the iterative and the noniterative synthase systems. Our results also establish the p-hydroxyphenylalkanoate extension ability of PpsA, the first-acting enzyme of a multisubunit noniterative polyketide synthase system. Notably, this noniterative system is also loaded with fatty acids by a specific fatty acyl-AMP ligase (FadD26) for biosynthesis of phthiocerol dimycocerosates (PDIMs), which are nonglycosylated lipids structurally related to PGLs. To our knowledge, the partially overlapping PGL and PDIM biosynthetic pathways provide the first example of two distinct, pathway-dedicated acyl-AMP ligases loading the same type I polyketide synthase system with two alternate starter units to produce two structurally different families of metabolites. The studies reported here advance our understanding of the biosynthesis of an important group of mycobacterial glycolipids.
