The Biological Roles of Steroid Sulfonation

Abstract

Although its role in mammalian physiology is currently underappreciated, sulfate is an obli‐ gate nutrient for numerous cellular and metabolic processes in human growth and develop‐ ment [1].The diet provides approximately one third of sulfate requirements in adults [2], although sulfate intake can vary greatly (1.5-16mmol/day) and is dependent on the source of drinking water (negligible to >500 mg/L) and types of food [3-5]. Brassica vegetables and commercial breads have a high sulfate content (>8.0umol/g) whereas low sulfate levels (<0.5umol/g) are found in some foods, including fresh onions, apples and oranges [5]. Once consumed, sulfate is absorbed through the intestinal epithelium into the blood, where it is maintained at approximately 0.3mM, making sulfate the fourth most abundant anion in hu‐ man circulation [6, 7]. Blood sulfate levels are maintained by the kidneys, which filter sulfate in the glomerulus and then reabsorb the majority of sulfate back into circulation [8]. The process of sulfate reabsorption occurs in the proximal tubule of the kidney, and is mediated by two sulfate transporter proteins, SLC13A1 (aka NaS1, Sodium sulfate transporter 1) and SLC26A1 (aka SAT1, Sulfate anion transporter 1) [9]. The NaS1 protein is expressed on the apical membrane of epithelial cells in the proximal tubule where it mediates the first step of sulfate reabsorption [10], and SAT1 mediates the second step across the basolateral mem‐ brane [11] (Figure 1A). Mice lacking the NaS1 or SAT1 genes have sulfate wasting into the urine which leads to low blood sulfate levels (hyposulfataemia) [12, 13]. Humans with loss of function mutations (R12X and N174S) in the NaS1 gene also exhibit renal sulfate wasting and hyposulfataemia [14]. This depletion of sulfate from circulation reduces sulfate availa‐ bility to cells throughout the body and leads to a reduced intracellular sulfate conjugation (sulfonation) capacity, as shown in the NaS1 and SAT1 null mice [12, 13, 15].