Sulfate groups can be found in several different species of organic molecules. In vertebrates, the highest density of sulfate groups is found in the proteoglycans, a broad category of macromolecules characterized by a core protein to which one to several hundred glycosaminoglycan side chains, composed of repeating units of sulfated disaccharides, are attached. Proteoglycans are present in most membranes and cell organelles, but they are particularly abundant in the extracellular matrix of connective tissues.
Biologic sulfation is performed by transferring sulfate from a universal high-energy sulfate donor, phosphoadenosine phosphosulfate (PAPS), to an acceptor substrate. Sulfation reactions are catalyzed by substrate-specific sulfotransferases. The availability of PAPS is rate-limiting in most sulfotransferase reactions. PAPS is synthesized in the cytoplasm from inorganic sulfate and ATP by a two-step reaction with adenosine phosphosulfate (APS) as an intermediate product.
Inorganic sulfate in the cytoplasm may be either imported from the extracellular fluid in exchange for chloride or produced within the cells by the oxidation of sulfur amino acids and other thiols. Cells with a high rate of proteoglycan synthesis, such as chondrocytes, depend on extracellular sulfate to replenish their cytoplasmic sulfate pool.
Deficiencies in specific sulfohydrolases responsible for the lysosomal degradation of sulfated proteoglycans and lipids produce genetic diseases classified under the mucopolysaccharidoses or leukodystrophies (see Chaps. 136 and 148). Genetic defects in the transmembrane transport or the metabolic activation of sulfate affect the synthesis rather than the degradation of proteoglycans and have been associated so far with skeletal dysplasias.
Mutations in a sulfate/chloride antiporter of the cell membrane, called diastrophic dysplasia sulfate transporter (DTDST), result in a family of skeletal dysplasias that comprises two lethal conditions, achondrogenesis 1B (ACG1B) (MIM 600972) and atelosteogenesis 2 (AO2), as well as two nonlethal conditions, diastrophic dysplasia (MIM 222600) and multiple epiphyseal dysplasia (MIM 226900). The inheritance of all these conditions is recessive. The cartilage of affected individuals contains proteoglycans with insufficient sulfation. Fibroblast and chondrocyte cultures of such individuals exhibit a defect in the uptake and incorporation of exogenous sulfate. The impairment in sulfate uptake in chondrocytes apparently leads to depletion of cytoplasmic sulfate and PAPS and to the synthesis of undersulfated proteoglycans.
A mutation in the ATPSK2 gene coding for the bifunctional enzyme ATP sulfurylase-APS kinase has been observed in several members of one family affected by recessively inherited spondyloepimetaphyseal dysplasia (SEMD).
A well-studied spontaneous mouse mutant called brachymorphic for the reduced length of its body and limbs is characterized by reduced sulfation of cartilage proteoglycans and by defective PAPS synthesis. The recently defined molecular basis is a missense mutation in the mouse ATPSK2 gene; brachymorphic is thus homologous to human ATPSK2-deficient SEMD.