Human disease, molecular basis

H5. Hudson, B. G., Reeder, S. T., and Tryggvason, K., Type IV collagen Structure, gene organization, and role in human diseases. Molecular basis of Goodpasture and Alport syndromes and diffuse leiomyomatosis. J. Biol. Chem. 268, 26033-26036 (1993). 

Burkhard P, Stetefeld J, Strelkov SV Coiled coils A highly versatile protein folding motif. Trends Cell Biol 2001 11 82. Collinge J Prion diseases of humans and animals Their causes and molecular basis. Annu RevNeurosci 2001 24 519. 

Surendran, S., Matalon, K. M., Tyring, S. K. etal. Molecular basis of Canavan s disease from human to mouse. /. Child Neurol. 18 604-610,2003. 

This is a beautiful example of how we can come to understand the molecular basis of an important human disease on the foundation of a few basic ideas about chemistry. 

In 1963 J.H. Rubinstein and H. Taybi reported a rare human disease that induced mental retardation, an increased risk of neoplasia and physical abnormalities, including broad thumbs, big and broad toes, short stature and craniofacial anomalies. The molecular basis of the Rubinstein-Taybi syndrome (RTS) was later discovered to be a disruption of one copy of the human CREB binding protein (CBP or CREB-BP) gene that encodes the histone acetyltransferase CBP [3]. In addition to CBP, all mammals have a closely related acetyltransferase, p300. Retrospectively, RTS was the first disease found to be due to a defective acetylation process [1-3]. 

Exploration of the molecular basis of human disease will continue to provide additional targets for drug discovery, while a better understanding of marine ecological interactions at the molecular level can be used to guide the selection of novel sources and novel screens. This multidisciplinary approach to discovery of marine-derived drugs will likely result in the continued discovery of unique bioactive chemical entities and new ways to address the treatment of human disease. 

The dictum in the traditional folklore of medicine has been the treatment and alleviation of acute symptoms of disease. Aforementioned advances in our understanding of the risk factors and molecular basis of human diseases are now paving the way to develop medicines that can prevent or slow the progression of disease phenomena. Schizophrenia and some of the neurodegenerative diseases such as Alzheimer s or Parkinson s disease... 

Section C Thomas, P.J., Qu, B.H. and Pederson, P.L. (1995) Defective protein folding as a basis of human disease. Trends Biochem. Sci. 20, 456-459. Wahl, M.C. and Sundaralingam, M. (1997) C-H...O hydrogen bonding in biology. Trends Biochem. Sci. 22, 97-102. Hampton, R., Dimster-Denk, D. and Rine, J. (1996) The biology of HMG-CoA reductase the pros of contra-regulation. Trends Biochem. Sci. 21, 140-145. Kantrowitz, E.R. and Lipscomb, W.N. (1990) Escherichia coli aspartate trans-carbamoylase the molecular basis for a concerted allosteric transition. Trends Biochem. Sci. 15, 53-59. 

While the current structural and functional studies have shed lights on the molecular mechanisms of post-receptor signal transduction by the TNFR superfamUy, many important questions remain. One such question is the structural basis for the formation of death receptor signaling complexes, involving DD-DD and DED-DED interactions. Another question is the molecular basis of TRAP downstream signaling. Does it involve oligomerization and proximity induced activation of down-stream effectors, or conformational modulations Because of the importance of the TNFR superfamily in human disease, an ultimate question lies on the translation of structural and functional studies into therapeutic applications. 

Reiners, J., Nagel-Wolfrum, K., Jurgens, K., Marker, T. and Wolfmm, U. (2006) Molecular basis of human Usher syndrome deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp. Eye Res. 83, 97-119. 

In summary, the marine environment contains a wealth of plants, animals and microorganisms. Due to their unique adaptations to their ocean habitat, they contain a wide diversity of natural products. These compounds have shown activity in a variety of assays which have relevance to human diseases. As our understanding of the molecular basis of disease expands, these compounds and ones yet to be discovered will provide lead compounds for human therapeutic treatment. Innovations in synthesis, fermentation of symbionts as well as in manipulation of biosynthetic genes will allow us to produce sufficient material for clinical use of the compounds. Marine organisms provide a unique opportunity for access to chemical diversity. 

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