A 47-year-old homeless man comes to the emergency department due to a "pins-and-needles" sensation in his legs. He also has painful lesions on his lips and corners of his mouth. He has had no loss of consciousness, nausea, vomiting, or diplopia. The patient drinks alcohol heavily on a daily basis and has a history of intravenous heroin use. On physical examination, he appears unkempt and ill appearing. Temperature is 36.8 C (98.2 F), blood pressure is 146/90 mm Hg, and pulse is 106/min. He has glossitis and angular stomatitis. Abdominal examination reveals hepatomegaly. Laboratory evaluation shows very low urinary riboflavin excretion. Activity of which of the following enzymes is most likely directly impaired in this patient?
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This patient's low urinary riboflavin excretion suggests a significant deficiency in riboflavin intake. Symptomatic riboflavin deficiency is rare in the United States but can be seen with chronic alcohol use and in severely malnourished patients. Clinical manifestations include angular stomatitis, cheilitis, glossitis, seborrheic dermatitis, eye changes (eg, keratitis, corneal neovascularization), and anemia.
The riboflavin (vitamin B2)-containing coenzymes are key constituents of the electron transport chain. Typically, riboflavin is first phosphorylated to become flavin mononucleotide (FMN), which can then be integrated into a coenzyme-flavin complex or further phosphorylated to flavin adenine dinucleotide (FAD). FMN and FAD participate as coenzymes in numerous reduction-oxidation reactions and are converted into reduced, energy-carrying states (FMNH2 and FADH2) through the acceptance of electrons.
FMN serves as a component of complex I, whereas FAD functions as a component of succinate dehydrogenase (complex II). Complex II participates in both the electron transport chain and tricarboxylic acid (TCA) cycle. During the TCA cycle, succinate dehydrogenase converts succinate to fumarate and transfers electrons to coenzyme Q (ubiquinone) via FAD. Complex II also accepts electrons from other sources of FADH2, such as fatty acid oxidation.
(Choices A, D, E, and G) Isocitrate dehydrogenase, succinate thiokinase, malate dehydrogenase, and fumarase are enzymes that participate in the TCA cycle but do not use FAD or FMN as cofactors.
(Choice B) Reduced glutathione is an antioxidant that minimizes oxidative damage in many cells. Glutathione reductase regenerates reduced glutathione using nicotinamide adenine dinucleotide phosphate (NADPH) as an electron donor and FAD as a cofactor. Although glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway and supplies the necessary NADPH, it does not use FAD as a cofactor.
(Choice C) HMG-CoA reductase is the rate-limiting enzyme in the cholesterol synthesis pathway. FMN and FAD are not used as cofactors.
Educational objective:
Riboflavin is a precursor of the coenzymes FMN and FAD. FAD participates in the tricarboxylic acid cycle and electron transport chain by acting as an electron acceptor for succinate dehydrogenase (complex II), which converts succinate into fumarate.