quantifying-binding-interactions-between-cu-ii-peptide-residues

Quantifying the Binding Interactions Between Cu(II) and Peptide Residues in the Presence and Absence of Chromophores

Copper(II) is an essential metal in biological systems, conferring unique chemical properties to the biomolecules with which it interacts. It has been ...

University of California, Davis

For over 100 years, there has been an incredible amount of knowledge amassed concerning hormones in the endocrine system and their central role in human health. Hormones represent a diverse group of biomolecules that are released by glands, communicate signals to their target tissue, and are regulated by feedback loops to maintain organism health. Many disease states, such as diabetes and reproductive disorders, stem from misregulation or dysfunction of hormones. Increasing research is illuminating the intricate roles of metal ions in the endocrine system where they may act advantageously in concert with hormones or deleteriously catalyze hormone-associated disease states. As the critical role of metal ions in the endocrine system becomes more apparent, it is increasingly important to untangle the complex mechanisms underlying the connections between inorganic biochemistry and hormone function to understand and control endocrinological phenomena. This tutorial review harmonizes the interdisciplinary fields of endocrinology and inorganic chemistry in the newly-termed field of "metalloendocrinology". We describe examples linking metals to both normal and aberrant hormone function with a focus on highlighting insight to molecular mechanisms. Hormone activities related to both essential metal micronutrients, such as copper, iron, zinc, and calcium, and disruptive nonessential metals, such as lead and cadmium are discussed.

Metal-dependent hormone function: the emerging interdisciplinary field of metalloendocrinology.

High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAF). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson's disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAF mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAF mutation compared to BRAF acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAF cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAF mutation.

Marie C. Heffern

Department of Chemistry

University of California, Davis

Quantifying the Binding Interactions Between Cu(II) and Peptide Residues in the Presence and Absence of Chromophores

Marie C. Heffern

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Chemistry

University of California, Davis

Quantifying the Binding Interactions Between Cu(II) and Peptide Residues in the Presence and Absence of Chromophores

Department of Chemistry