9.1 Monosaccharide Metabolism

Fructose metabolism

Fructose is a dietary component of sucrose in fruit, as a free sugar in honey, and in high-fructose corn syrup. It is taken up by cells through facilitated diffusion through the GLUT5 transporter. Fructose is metabolized principally in the liver, and the initial step involves phosphorylation at the 1-position to form fructose 1-phosphate (figure 9.1). Fructokinase, the major kinase involved, phosphorylates fructose in the 1-position. Fructokinase has a high V_max and rapidly phosphorylates fructose as it enters the cell. Aldolase B cleaves fructose 1-phosphate into glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate, which can enter directly into glycolysis.

Aldolase B is the rate-limiting enzyme of fructose metabolism, although it is not a rate-limiting enzyme of glycolysis. Aldolase B’s affinity for fructose 1-phosphate is lower than fructose 1,6-bisphosphate and is very slow at physiological levels of fructose 1-phosphate. Consequently, after high fructose consumption, fructose 1-phosphate will accumulate in the liver, and it is slowly converted to glycolytic intermediates over time (figures 9.1 and 9.2).

Deficiencies in fructose metabolism

Essential fructosuria (fructokinase deficiency) and hereditary fructose intolerance (HFI) (a deficiency of the fructose 1-phosphate cleavage by aldolase B) are inherited disorders of fructose metabolism. A deficiency in fructokinase is a benign genetic disorder. In this case, an individual will have fructosuria; fructose is not phosphorylated and trapped in the cell. Consequently, any ingested fructose is shed in the urine. Hereditary fructose intolerance is caused by a deficiency in aldolase B and results in an accumulation of fructose 1-phosphate in the hepatocytes. Inability to metabolize fructose 1-phosphate can cause significant clinical symptoms, most notably hepatomegaly and fasting hypoglyemia. The accumulation of fructose 1-phosphate eventually inhibits both glycogenolysis and gluconeogenesis (due to a lack of free phosphate), leading to bouts of fasting hypoglycemia.

Galactose metabolism

Galactose is consumed principally as lactose, which is cleaved to galactose and glucose in the intestine. Galactose is subsequently phosphorylated to galactose 1-phosphate by galactokinase (primarily in the liver). Following phosphorylation, galactose 1-phosphate is activated to a uridine diphosphate (UDP)-sugar by galactosyl uridylyltransferase (GALT). The metabolic pathway subsequently generates glucose 1-phosphate, which enters into the glycolytic pathway (figure 9.2)

Deficiencies in galactose metabolism

Classical galactosemia, a deficiency of galactosyl uridylyltransferase (GALT), results in the accumulation of galactose 1-phosphate in the liver and the inhibition of hepatic glycogen metabolism and other pathways that require UDP-sugars. Cataracts can occur from the accumulation of galactose in the blood, which is converted to galactitol (the sugar alcohol of galactose) in the lens of the eye.

The accumulating galactose 1-phosphate is especially toxic for the liver, kidneys, and central nervous system. If left untreated, the disease is fatal due to complications such as gram-negative sepsis or hepatic and renal failure. The absence of GALT activity can be detected any time after birth and screened for as part of newborn screening. It is essential to obtain results promptly, because children with classic galactosemia can have a life-threatening crisis within the first few days after birth. Infants with a positive result are placed on a lactose-free formula, and confirmatory testing is accomplished by measuring specific metabolite concentrations and enzyme activity in erythrocytes.

Nonclassical galactosemia causes fewer medical complications and presents with a different pattern of symptoms. Presentations can involve cataracts, delayed development, and kidney problems.

9.2 Alcohol Metabolism

Metabolism of alcohol occurs primarily in the liver through two different oxidative pathways. The activity of each pathway depends on the ethanol concentration and the frequency of ethanol consumption.

At low concentrations, oxidation of ethanol is a two-step process that occurs in both the cytosol and the mitochondria (figure 9.5). The first step of the reaction by alcohol dehydrogenase (ADH) occurs in the cytosol and produces acetaldehyde. Acetaldehyde is converted into acetate in the mitochondria by acetaldehyde dehydrogenase (ALDH) and can be transported in the blood to be used as an energy source for peripheral tissues (figure 9.5). The acetate can be converted to acetyl-CoA by acetyl-CoA synthetase (figure 9.6), and this will be oxidized in the TCA cycle. Each step in the oxidation of ethanol produces NADH, which increases the ratio of NADH/NAD⁺. The increase in this ratio can alter metabolism of other substrates and cause metabolic dysfunction, which will be discussed below.

Consequences of ethanol metabolism in the liver

At each step in ethanol oxidation, NADH is generated in both the mitochondrial and cytosolic compartments (figure 9.5). This can have major metabolic ramifications depending on the underlying metabolic environment (figure 9.7).

1. Hypoglycemia: High NADH produced by alcohol metabolism (figure 9.7; label 1) contributes to the diversion of the gluconeogenic substrates OAA and pyruvate. The higher NADH/NAD⁺ ratio drives the reactions toward malate and lactate, respectively. This can lead to the presentation of fasting hypoglycemia (figure 9.7; labels 4, 6, and 8).
2. Fatty steatosis: High NADH/NAD⁺ ratio also increases the conversion of dihydroxyacetone phosphate to glycerol 3-phosphate, contributing to increased synthesis of triacylglycerol. Additionally, increases in reactive oxygen species, which can impair protein synthesis, prevent the assembly and secretion of VLDLs. This can ultimately contribute to fatty liver disease (figure 9.7; label 3).
3. Acidosis: Increases in alternative substrates for peripheral tissues (acetate from alcohol oxidation) can cause an elevation of ketones leading to ketoacidosis (figure 9.7; label 5).
4. Hyperlipidemia: The elevated NADH will negatively impact flux through the TCA by reducing the activity of the two key regulatory enzymes. This can lead to an increased shunting of citrate for fatty acid synthesis (figure 9.7; labels 2 and 3).
5. Acetaldehyde is a toxic compound that forms adducts with other proteins reducing their ability to function.

Excessive alcohol consumption

At higher concentrations of ethanol, the microsomal ethanol oxidizing system (MEOS) becomes activated (figure 9.7; label 9). This pathway consists of a series of cytochrome P450 enzymes, which have a relatively high K_m for ethanol and are located in the hepatic smooth endoplasmic reticulum (SER). This microsomal-ethanol oxidizing system also detoxifies drugs such as barbiturates (figure 9.8).

1. Chronic consumption of alcohol will increase the expression of the MEOS and proliferation of hepatic SER. Increases in expression of both CYP2E1 (P450 enzyme) and γ-glutamyltransferase (GGT), an enzyme located in the SER, are excellent markers of alcohol ingestion.
2. Ethanol oxidation by MEOS does not affect the NADH/NAD⁺ ratio substantially, therefore, it does not have the metabolic effects described for low concentrations of ethanol.

Although the MEOS system does not impact the NADH/NAD⁺ ratio, that is not to suggest that induction of this system is without metabolic consequences. Induction of the P450 system can negatively impact the metabolism of other drugs causing serious side effects. One example of this is altered metabolism of acetaminophen (Tylenol). Acetaminophen can be glucuronylated or sulfated in the liver for safe excretion by the kidney. However, the cytochrome P450 system can metabolize acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI), which requires conjugation with glutathione prior to excretion. The enzyme that produces NAPQI, CYP2E1, is induced by alcohol through the MEOS. Thus, individuals who chronically abuse alcohol have increased sensitivity to acetaminophen toxicity because a higher percentage of acetaminophen metabolism is directed toward NAPQI, compared with an individual with low levels of CYP2E1.

Ethanol is also an inhibitor of the phenobarbital-oxidizing P450 system. When large amounts of ethanol are consumed, the inactivation of phenobarbital is directly or indirectly inhibited. Therefore, when high doses of phenobarbital and ethanol are consumed at the same time, toxic levels of the barbiturate can accumulate in the blood.