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Marc J. Glucksman, Ph.D.

Professor & Chair, Biochemistry
and Molecular Biology
Director, Midwest Proteome Center

Chicago Medical School
Biochemistry and Molecular Biology
Room: 3.162/3.176
Building: BSB
Phone: 847.578.3235
Fax: 847.578.3240
Current Research:

The degradation and/or processing of bioactive peptides is one of the most prevalent and efficient modes of physiologic regulation.  My research program involves examination of structure-activity relationships at the atomic level of the enzymes and neuropeptide substrates of several reactions involved in the normal and disease states of neurobiological, aging and reproductive processes.  Molecular biological methods are utilized for the generation and expression of wild type and mutagenized proteins in large quantities and cloning related enzymes while the biophysical techniques of X-ray diffraction and spectroscopy elucidate the structural detail of these macromolecules.  The results of these methodologies are coupled with computer-aided modeling with homologous metalloproteases to design rational functional correlates which are then tested physiologically, and may result in better designed therapeutics.  The mammalian zinc metalloendopeptidase EC [EP 24.15], is crucial to the formation and degradation of many bioactive peptides.  EP 24.15 can control mammalian reproduction through its regulation of the pivotal neuropeptide, the decapeptide gonadotropin releasing hormone [GnRH].  EP 24.15 also acts upon small peptide substrates: neurotensin, substance P, bradykinin and generating bioactive enkephalins from precursor proteins.  Additional roles of this enzyme's involvement in neuropsychiatric disorders are: the ability to produce amyloidogenic peptides in Alzheimer's disease and an involvement in schizophrenia mediated by neuropeptides acting on glutamate receptors during puberty.

View of the active site of EP24.15 from the initial averaged model.  The proposed active site of the enzyme includes the conserved four helix bundle and loops containing invariant sidechains.

A.  ALZHEIMER'S DISEASE - EP24.15 immunoreactivity with regions containing large pyramidal
neurons in hippocampus, as well as layers 3 and 5 of the cortex.
B.  EP24.15 Immunoreactive in amyloid deposits and intense staining of the dystrophic neurites.

PROTEOMICS - Involves a broad-based, novel mass screening procedure to identify markers and assess structure-function relationships for diagnostics, risk factors and targets for treatment of Alzheimer's Disease, schizophrenia and endocrine cancers (e.g. prostate).  New markers, notable for their diagnostic potential and prognostic values, are sought.  An optimal approach is delineation of the expressed proteins for markers from human tissue and matched controls (including urine and serum) from tissue banks representing characterized patient populations.  In the case of prostate cancer, initial proteomic analyses utilize cell models amenable to subcellular fractionation.  We can enrich for low abundance proteins by searching components of media for secreted proteins and/or membranes for specific cell surface probes.  Proteome (protein complement of the genome) paradigms commence through examining protein expression between disease and normal tissues (or cell lines).  A given gene can produce more than one functional protein by: differential mRNA splicing and post-translational modifications (e.g. phosphorylation, glycosylation).  Proteins are separated by 2D gel electrophoresis and changes in quantity or migration of proteins are located, quantified, excised, digested, and analyzed by mass spectroscopy.  With potential "hits" from both gene and protein analyses, we utilize the approaches delineated above to identify and structurally assess proteins by X-ray crystallography as well as by defining "functional" changes present in the development and progression of diseases.

STRUCTURE-FUNCTION CORRELATES IN GENE DISCOVERY - Structure-Function Assessment and Molecular Modeling in Various Genetic Disorders: In collaboration with the Martignetti Lab at Mt. Sinai, my group utilizes computer-aided protein modeling as well as molecular biology/biochemistry and X-ray crystallographic approaches to explain the phenotype of mutations in non muscle myosin platelet disorders [May-Heggelin, Fechtner, and Sebastian; the first use of the complete chromosome 22 sequence from the Human Genome Project]. Another project involves the matrix metalloprotease 2 (MMP-2), and its involvement in a syndromic osteolysis/arthritis.  This is the first proven disorder in which a matrix metalloprotease is involved and that proteolysis of extracellular matrix mediates human growth and development.  In addition to molecular modeling, expression of wild type and mutant MMP-2's are evaluated for differences in their X-ray structures and kinetic characteristics towards developing therapeutics.  Lastly, a putative tumour suppressor, KLF6, was assessed for potential functionality and mutants in prostate cancer assessed by the gene discovery/structure function correlate approach.  Validation of these novel gene products is proceeding with proteomics and knock-in paradigms. 

Life in Discovery
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