Glyoxalase activity in human erythrocytes and mouse lymphoma, liver and brain probed with hyperpolarized 13C-methylglyoxal

Abstract

Methylglyoxal is a faulty metabolite. It is a ubiquitous by-product of glucose and amino acid metabolism that spontaneously reacts with proximal amino groups in proteins and nucleic acids, leading to impairment of their function. The glyoxalase pathway evolved early in phylogeny to bring about rapid catabolism of methylglyoxal, and an understanding of the role of methylglyoxal and the glyoxalases in many diseases is beginning to emerge. Metabolic processing of methylglyoxal is very rapid in vivo and thus notoriously difficult to detect and quantify. Here we show that 13C nuclei in labeled methylglyoxal can be hyperpolarized using dynamic nuclear polarization, providing 13C nuclear magnetic resonance signal enhancements in the solution state close to 5,000-fold. We demonstrate the applications of this probe of metabolism for kinetic characterization of the glyoxalase system in isolated cells as well as mouse brain, liver and lymphoma in vivo.

Detection of glucose-derived d- and l-lactate in cancer cells by the use of a chiral NMR shift reagent

“…Although the method is quantitative, it is not easily adapted to routine measures of d - and l -lactate in biological samples. Hyperpolarized 13 C-labeled MG has also been used to detect d -lactate as an end-product of the glyoxalase pathway in RBCs, in EL4 tumor-bearing mice, and in the liver and brain of live animals [ 13 ]. This exciting observation demonstrates that the glyoxalase pathway is active in these tissues, but it does not allow measurement of the relative amounts of d -lactate versus l -lactate produced in those tissues without the addition of exogenous MG in supraphysiological quantities.…”

Comment on mr-2021-14

“…Detection of hyperpolarized NMR/MRI signals typically occurs in a magnetic field range of 1.5-9.4 T, thus Fig. 3(b) indicates a 13 C nuclear T1 of the order of ~60 s for a carbonyl group, and this is commonly seen in practice (Shishmarev et al, 2018a). It is important to remember that Eqs.…”

“…Small molecules containing 13 C atoms that do not have directly bonded 1 H, or at least 1 H spins located at significant internuclear distances, are required. Such moieties include the carboxyl group that is present in many low molecular weight metabolites such as pyruvate, lactate, and methylglyoxal (Shishmarev et al, 2018a). At the longer 1 H-13 C internuclear distance of 1.45 Å, implying a 1 H-13 C dipole-dipole coupling constant of /2 = −10.2 kHz, a 13 C nuclear T1 of ~60 s is predicted.…”

Comprehensive Literature Review of Hyperpolarized Carbon-13 MRI: The Road to Clinical Application

“…This review focuses on the clinical transition; therefore, areas other than those listed in the previous sections (e.g., lung [ 132 , 133 ], angiography [ 134 ], placenta [ 135 , 136 ], muscle [ 137 , 138 , 139 ]), diseases (e.g., diabetes [ 63 , 140 , 141 , 142 ], rheumatoid arthritis [ 143 , 144 ], toxin-induced neuroinflammation [ 145 ], radiation injury [ 146 , 147 ]), and physiology (e.g., cell metabolism [ 148 , 149 ], pH [ 130 ], blood serum [ 150 , 151 ], bacteria metabolism [ 152 ]) are not be covered.…”