Red blood cell metabolism and enzyme defects

After enucleation, red blood cell (RBC) metabolism is maintained by mitochondria, a short supply of residual mRNA, and preformed enzymes. Glucose, which enters RBCs in an insulin-independent fashion, is catabolized via the anaerobic Embden-Meyerhof-Parnas glycolytic pathway . Because the aerobic citric acid cycle does not function in the RBCs, both end products of glycolysis (pyruvate and lactate) are released into the blood. Glycolysis yields a net energy gain of two molecules of adenosine triphosphate (ATP) per molecule of glucose. This energy is primarily used by the RBCs to maintain osmotic equilibrium and membrane integrity. Glycolysis also yields reducing power (from nicotinamide adenine dinucleotide plus hydrogen [NADH] and nicotinamide adenine dinucleotide phosphate [NADPH]) that can be used to reverse oxidant damage sustained by RBCs.

Three important auxiliary metabolic pathways branch from the glycolytic pathway: the hexose monophosphate (HMP) shunt , the 2,3-bisphosphoglycerate (2,3-BPG) pathway, and the methemoglobin reductase pathway ( Fig. 6.1 ).

Open full size image

Erythrocyte metabolism. Red blood cells need energy to maintain heme iron in reduced Fe ²⁺ form, to maintain reduced sulfhydryl groups in proteins, to preserve the osmotic gradient with ion pumps, and to prevent oxidation of membrane lipids. Asterisks mark enzymes for which deficiency is associated with hemolytic anemia. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; G6PD, glucose-6-phosphate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide plus hydrogen; NADPH, nicotinamide adenine dinucleotide phosphate; RBC, red blood cell.

The HMP shunt , by converting NADP to its reduced form, NADPH, replenishes the supply of glutathione , a sulfhydryl-containing tripeptide that serves as a protective reducing agent in RBCs by inactivation of hydrogen peroxide and reduction of oxidized proteins, including hemoglobin. The first reaction in the HMP shunt, the conversion of glucose-6-phosphate to 6-phosphogluconolactone, is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD) .

Under conditions of hypoxia or acidosis, oxygen delivery to tissues is enhanced by a reduction in hemoglobin oxygen affinity due to reversible binding of 2,3-BPG to hemoglobin. The conversion of 1,3-BPG to 2,3-BPG leads to reduced hemoglobin oxygen affinity at the expense of one molecule of ATP. Increased 2,3-BPG deoxyhemoglobin with greater affinity than oxyhemoglobin, leading to more rapid oxygen delivery to hypoxic tissues.

Methemoglobin , a nonfunctional hemoglobin variant formed by oxidation of heme iron from the ferrous to the ferric state, is normally reconverted to hemoglobin by NADH-dependent methemoglobin reductase—a complex of flavine adenine dinucleotide (FAD) and cytochrome b5. The source of the NADH (reduced NAD) is the glycolytic conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate.