Protein-Metabolite Interactions: Discovery and Significance.

Metabolites orchestrate cellular processes as either substrates, co-enzymes, inhibitors, or activators of cellular proteins such as enzymes and receptors. Although traditional biochemical and structural biology-based approaches have been successfully employed for the discovery of protein-metabolite interactions, they often fail to detect transient and low-affinity biomolecular relationships. Another limitation of these approaches is that they are performed under in vitro conditions lacking the physiological context. Recently developed mass spectrometry-based methodologies overcome both these shortcomings, and have resulted in the discovery of global protein-metabolite cellular interaction networks. Herein, we describe traditional and modern approaches for the discovery of protein-metabolite interactions, and discuss the impact of these discoveries on our understanding of cellular physiology and on drug development.

Metabolic Labeling-Based Chemoproteomics Establishes Choline Metabolites as Protein Function Modulators.

Choline is an essential nutrient for mammalian cells. Our understanding of the cellular functions of choline and its metabolites, independent of their roles as choline lipid metabolism intermediates, remains limited. In addition to fundamental cellular physiology, this knowledge has implications for cancer biology because elevated choline metabolite levels are a hallmark of cancer. Here, we establish a mammalian choline metabolite-interacting proteome by utilizing a photocrosslinkable choline probe. To design this probe, we performed metabolic labeling experiments with structurally diverse choline analogues that resulted in the serendipitous discovery of a choline lipid headgroup remodeling mechanism involving sequential dealkylation and methylation steps. We demonstrate that phosphocholine inhibits the binding of one of the proteins identified, the attractive anticancer target p32, to its endogenous ligands and to the promising p32-targeting anticancer agent, Lyp-1. Our results reveal that choline metabolites play vital roles in cellular physiology by serving as modulators of protein function.

Isolated Sixth Nerve Palsy as the First Manifestation of Cavernous Sinus Metastasis From Primary Breast Cancer.

Cavernous sinus metastasis is a rare clinical finding, presenting most commonly with complaints of headache, diplopia, visual field defects, facial pain, and progressive neurological deficits. Many patients present with features of III, IV, and VI nerve palsies. We hereby report an unusual case of cavernous sinus metastasis from primary breast cancer in a 40-year-old female, who presented with binocular diplopia due to left VI nerve palsy as the first presenting complaint. The patient had a history of surgery for left breast cancer which was performed at another center. Contrast-enhanced computed tomography (CECT) scan of thorax and abdomen revealed a residual neoplastic left breast mass with satellite nodules, left axillary lymphadenopathy, and hepatic, splenic, and skeletal metastasis. Contrast-enhanced magnetic resonance imaging (CE-MRI) of brain and orbit showed enhancing lesion of 20 mm x 10 mm along the lateral wall of left cavernous sinus and left petrous apex. She was referred to radiation oncology department for further management. This case report highlights the importance of ophthalmologists in such life-threatening conditions, who may first present to them.