Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: Cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low HDL-C levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent 2 kidney and one liver transplantations. Results show that elevated TG and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.

Biochemical Approaches to Probe the Role of the Auxiliary Iron-Sulfur Cluster of Lipoyl Synthase from Mycobacterium Tuberculosis.

Lipoic acid is an essential sulfur-containing cofactor used by several multienzyme complexes involved in energy metabolism and the breakdown of certain amino acids. It is composed of n-octanoic acid with sulfur atoms appended at C6 and C8. Lipoic acid is biosynthesized de novo in its cofactor form, in which it is covalently bound in an amide linkage to a target lysyl residue on a lipoyl carrier protein (LCP). The n-octanoyl moiety of the cofactor is derived from type 2 fatty acid biosynthesis and is transferred to an LCP to afford an octanoyllysyl amino acid. Next, lipoyl synthase (LipA in bacteria) catalyzes the attachment of the two sulfur atoms to afford the intact cofactor. LipA is a radical S-adenosylmethionine (SAM) enzyme that contains two [4Fe-4S] clusters. One [4Fe-4S] cluster is used to facilitate a reductive cleavage of SAM to render the highly oxidizing 5'-deoxyadenosyl 5'-radical needed to abstract C6 and C8 hydrogen atoms to allow for sulfur attachment. By contrast, the second cluster is the sulfur source, necessitating its destruction during turnover. In Escherichia coli, this auxiliary cluster can be restored after each turnover by NfuA or IscU, which are two iron-sulfur cluster carrier proteins that are implicated in iron-sulfur cluster biogenesis. In this chapter, we describe methods for purifying and characterizing LipA and NfuA from Mycobacterium tuberculosis, a human pathogen for which endogenously synthesized lipoic acid is essential. These studies provide the foundation for assessing lipoic acid biosynthesis as a potential target for the design of novel antituberculosis agents.