Nancy B Schwartz

One area of interest focuses on how the machinery for sulfation, a common posttranslational modification of proteins, lipids and carbohydrates is organized and controlled in higher organisms. The integrated pathway for sulfate uptake, activation and utilization encompasses multiple components and multiple intracellular compartments. At the center of this process is the bifunctional PAPS synthetase which synthesizes phosphoadenosylphosulfate (PAPS) from ATP and SO42- in a two-step process, catalyzed by ATP-sulfurylase and APS-kinase activities. We discovered the PAPS synthetase gene family, identified mutations in PAPS synthetase that lead to both human and animal chondrodystrophies and elucidated unique enzymatic properties, including channeling of the intermediate APS more recently using i) a systems approach, we have identified a trifunctional single polypeptide enzyme which includes a pyrophosphotase activity; ii) loss-and-gain of function models, we have determined that defects in PAPS-synthetase, resulting in an undersulfated matrix in some tissues, causes aberrant trafficking and signaling of secreted morphogens. Overall, the long-term goal is to provide a model of the temporal and topological organization of this critically important pathway, how it is regulated, and to correlate defects in the overall pathway with abnormal growth and development. Our new findings open up a new field focused on regulation of key morphogens by the extracellular environment, whose composition is partly determined by PAPS synthetase, and through which they must migrate to deliver signals from source to target cells.

One area of interest focuses on how the machinery for sulfation, a common posttranslational modification of proteins, lipids and carbohydrates is organized and controlled in higher organisms. The integrated pathway for sulfate uptake, activation and utilization encompasses multiple components and multiple intracellular compartments. At the center of this process is the bifunctional PAPS synthetase which synthesizes phosphoadenosylphosulfate (PAPS) from ATP and SO42- in a two-step process, catalyzed by ATP-sulfurylase and APS-kinase activities. We discovered the PAPS synthetase gene family, identified mutations in PAPS synthetase that lead to both human and animal chondrodystrophies and elucidated unique enzymatic properties, including channeling of the intermediate APS more recently using i) a systems approach, we have identified a trifunctional single polypeptide enzyme which includes a pyrophosphotase activity; ii) loss-and-gain of function models, we have determined that defects in PAPS-synthetase, resulting in an undersulfated matrix in some tissues, causes aberrant trafficking and signaling of secreted morphogens. Overall, the long-term goal is to provide a model of the temporal and topological organization of this critically important pathway, how it is regulated, and to correlate defects in the overall pathway with abnormal...

Cortes M, Baria AT, Schwartz NB. (2009) Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development, 136: 1697-706.  

Bradley ME, Rest JS, Li WH, Schwartz NB. (2009) Sulfate activation enzymes: phylogeny and association with pyrophosphatase. J Mol Evol. 68: 1-13.  

King LA, Schwartz NB, Domowicz MS. (2009) Glial migratory streams in the developing hindbrain: a slice culture approach. J Neurosci Methods. 177: 30-43.  

Domowicz MS, Sanders TA, Ragsdale CW, Schwartz NB. (2008) Aggrecan is expressed by embryonic brain glia and regulates astrocyte development. Dev Biol. 315: 114-24.  

Schwartz NB, Cortes M, King LA. (2007) Got sulfate? Luring axons this way and that. Chem Biol. 14: 119-20.  

Pirok EW 3rd, Domowicz MS, Henry J, Wang Y, Santore M, Mueller MM, Schwartz NB. (2005) APBP-1, a DNA/RNA-binding protein, interacts with the chick aggrecan regulatory region. J Biol Chem. 280: 35606-16.  

Schwartz NB, Domowicz M. (2004) Proteoglycans in brain development. Glycoconj J. 21: 329-41.  

Domowicz M, Mueller MM, Novak TE, Schwartz LE and Schwartz NB. (2003) Developmental expression of the HNK-1 carbohydrate epitope on aggrecan during chondrogenesis. Devel. Dynamics, 226:42-50. 

Domowicz M, Mangoura J, Schwartz NB. (2003) Aggrecan regulates telencephalic neuronal aggregation in Culture. Dev. Brain Res, 143:207-216.  

Schwartz NB and Domowicz, MS. (2004) Chondrodysplasias. Encyclopedia of Endocrine Diseases, Elsevier Science, 1, 502-509. 

Schwartz NB and Domowicz, MS. (2004) Proteoglycans in Brain Development. Glycoconjugate J. 21:327-339.  

Schwartz NB and Domowicz, MS. (2004) Chondrodysplasias. Encyclopedia of Endocrine Diseases, Elsevier Science, 1, 502-509. 

Schwartz NB. (2005) PAPS and Sulfoconjugation, Human Cystolic Sulfotransferases. London: Taylor and Francis, 43-57 

Pirok E, Domowicz M, Henry J, Wang Y, Santore M, Mueller M and Schwartz NB. (2005) ARBP-I, A DNA/RNA binding protein, interacts with the chick aggrecan regulatory region. J Biol Chem 280:35606-35616. 

Schwartz NB. Sulfation: The last steps in synthesis of proteoglycans. Trends in Glycoscience and Glycotechnology, in press. 

Cortes M, Baria AT, Schwartz NB. (2009) Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development, 136: 1697-706.  

Bradley ME, Rest JS, Li WH, Schwartz NB. (2009) Sulfate activation enzymes: phylogeny and association with pyrophosphatase. J Mol Evol. 68: 1-13.  

King LA, Schwartz NB, Domowicz MS. (2009) Glial migratory streams in the developing hindbrain: a slice culture approach. J Neurosci Methods. 177: 30-43.  

Domowicz MS, Sanders TA, Ragsdale CW, Schwartz NB. (2008) Aggrecan is expressed by embryonic brain glia and regulates astrocyte development. Dev Biol. 315: 114-24.  

Schwartz NB, Cortes M, King LA. (2007) Got sulfate? Luring axons this way and that. Chem Biol. 14: 119-20.