Endogenous Production

Endogenous production of HMB occurs in muscle and liver1718 (Figure 12.1) and possibly other tissues. The first step in HMB formation is the transamination of leucine to KIC, which occurs in both the cytosol and mitochondria of muscle cells.19 In the mitochondria, KIC is irreversibly oxidized to isovaleryl-CoA by the enzyme branched-chain a-keto acid dehydrogenase. Isovaleryl-CoA then undergoes further metabolic steps within the mitochondria (Figure 12.1), yielding P-hydroxy-P-methylglutaryl-CoA (HMG-CoA). Further metabolism by the enzyme HMG-CoA lyase results in the end products acetoacetate and acetyl-CoA. Approximately 90% of KIC is oxidized to isovaleryl CoA in liver mitochondria and ultimately to acetoacetate and acetyl-CoA.

In the cytosol of cells, the remaining ~10% of the KIC is oxidized to HMB20-24 via the enzyme KIC dioxygenase. This enzyme requires molecular oxygen and iron,24 and may be identical to p-phenylpyruvate dioxygenase, which is a key enzyme in the degradation of tyrosine converting 4-hydroxyphenylpyrvate to homogentisate.25

A second pathway in the production of HMB has also been postulated through the hydroxylation of methylcrotenoic acid (MCA), but only when biotin is deficient. It is proposed that MCA concentrations become elevated due to the low activity of the biotin-requiring enzyme MC-CoA carboxylase. HMB levels also increase,26 suggesting that MCA may be hydrated to HMB by enol-CoA hydrase,27 an enzyme of the isoleucine pathway. However, it is not clear whether MCA is directly converted to HMB during biotin deficiency, or if the rise in HMB is simply a result of feedback inhibition on the various enzymes along the pathway back to KIC.

Extrapolating from leucine turnover studies in pigs,28 it is estimated that endogenous HMB production is equal to 0.2 to 0.4 g of HMB/day in a 70-kg man, depending on leucine intake. Furthermore, turnover of HMB is thought to be relatively rapid, as basal plasma concentrations in normal humans range from 1 to 4 nM.2930 Plasma levels of

LEUCINE

Branched chain amino acid transferase (muscle)

'a-Ketoglutarate-

glutamate t_

a-Ketoisocaproate (KIC) p alanine pyruvate

Branched chain a-ketoacid dehydrogenase-mitochondria (liver)

Branched chain amino acid transferase (muscle)

glutamate t_

Branched chain a-ketoacid dehydrogenase-mitochondria (liver)

Isovaleryl-CoA

-methyl-crotonyl-CoA (MC-CoA)

FIGURE 12.1 Overview of leucine, a-ketoisocaproate (KIC), and p-hydroxy-p-methyl-butyrate (HMB) metabolism.

Isovaleryl-CoA

Isovaleryl-CoA dehydrogenase

-methyl-crotonyl-CoA (MC-CoA)

MC-CoA-carboxylase

  • methyl-gluconyl-CoA (MG-CoA)
  • H 2 O MG-CoA-hydrase
  • hydroxy-p-methylglutaryl-CoA (HMG-CoA)
  • HMG-CoA-lyase (liver)

Acetoacetate +Acetyl-CoA

FIGURE 12.1 Overview of leucine, a-ketoisocaproate (KIC), and p-hydroxy-p-methyl-butyrate (HMB) metabolism.

HMB increase following ingestion of 1 g of HMB to approximately 115 nM, but are near basal levels 12 h later, again suggesting rapid metabolism.

12.1.2 Fate

HMB has two fates in the body: conversion to HMG-CoA31-33 and excretion in the urine.28-30 The metabolic pathway of HMB metabolism is conversion to HMG-CoA (Figure 12.1). In the cytosol, conversion of HMB to HMG-CoA occurs either through direct carboxylation or through dehydration of MCA-CoA (Figure 12.1). Subsequently, the cytosolic HMG-CoA produced can provide substrate for HMG-CoA reductase, which is the committed step in cellular cholesterol synthesis.4 This fact has been hypothesized as a mechanism whereby HMB can affect cellular metabolism by providing a cholesterol precursor during times of elevated need.4

Urinary excretion of HMB in humans ranges from 10% to almost 50% of an exogenous HMB dosage.4 Nissen et al.3 reported that urine HMB excretion varied from 10 to 30 mg/day prior to supplementation, while supplementation of 1.5 and 3.0 g of HMB/day resulted in an increase in excretion to 450 to 500 mg/day and 950 to 1200 mg/day, respectively. Recent metabolic studies following ingestion of 1 g of HMB resulted in approximately 14% of the given dose being excreted in the urine. The percentage of the dosage excreted increased to 29% of the given dose after consumption of a single 3-g dose of HMB.29 With both dosages of HMB given, most of the urinary excretion occurred within 6 h of the dosing, paralleling the increases in plasma HMB.29

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