Conversion of pyruvate to ethanol by certain yeast
strains occurs in two steps. It is first decarboxylated to
acetaldehyde by pyruvate decarboxylase, which utilizes
thiamine pyrophosphate (TPP) as coenzyme.
--- ►
CHO + C 0
In the second step, acetaldehyde is reduced to ethanol by
alcohol dehydrogenase, an NAD-dependent enzyme.
The NADH is derived from glyceraldehyde 3-phosphate
dehydrogenation. Thus, yeast fermentation yields ethanol
rather than lactate as an end product of glycolysis. Small
amounts of ethanol are produced by the microbial flora of
the gastrointestinal tract. Other types of fermentation using
similar reactions occur in microorganisms and yield a va-
riety of products (e.g., acetate, acetone, butanol, butyrate,
isopropanol, hydrogen gas).
Lactic Acidemia and Lactic Acidosis
As discussed earlier, some tissues produce lactate as
an end product of metabolism. The lactate produced is
L-lactate and is commonly referred to simply as lactate. As
we will see in the following discussion, D-lactate is also
produced under certain pathological conditions, which
presents a unique clinical problem.
Under normal conditions, lactate is metabolized in the
liver and the blood lactate level is between 1
and 2 mM.
Lactate accumulation in body fluids can be due to in-
creased production and/or decreased utilization. Blood
lactate-to-pyruvate ratio below 25 suggests defects in a
gluconeogenic enzyme (Chapter 15) or pyruvate dehydro-
genase (discussed later). A common cause of
lactic aci-
is tissue hypoxia caused by shock, cardiopulmonary
arrest, and hypoperfusion. Inadequate blood flow leads to
deprivation of oxygen and other nutrients to the tissue cells
as well as to the removal of waste products. Oxygen de-
privation leads to decreased ATP production and accumu-
lation of NADH, which promotes conversion of pyruvate
to lactate.
A major cause of acidosis that occurs during inade-
quate cellular oxygen delivery is continual hydrolysis of
the available supply of ATP that releases protons:
ATP4“ + H20 -> ADP3" + HPO3“ + H+
Laboratory assessment includes measurements of blood
lactate, pyruvate, /bhydroxybutyrate, and acetoacetate
(Chapter 39). The primary treatment of lactic acidosis in-
volves correcting the underlying cause such as reversal of
circulatory failure.
D-Lactic Acidosis
This unusual form of lactic acidosis is due to increased
production and accumulation of D-lactate in circulation.
The normal isomer synthesized in the human body is
L-lactate but the D-lactate isomer can occur in patients
with jejunoileal bypass, small bowel resection, or other
types of short bowel syndrome. In these patients, ingested
starch and glucose bypass the normal metabolism in the
small intestine and lead to increased delivery of nutrients
to the colon where gram-positive, anaerobic bacteria (e.g.,
ferment glucose to D-lactate. The D-lactate
is absorbed via the portal circulation.
A limited quantity of D-lactate is converted to pyru-
vate by a mitochondrial flavoprotein enzyme D-2-hydroxy
acid dehydrogenase. Thus, the development of D-lactate
acidosis requires excessive production of D-lactate and
an impairment in its metabolism. The clinical manifes-
tations of D-lactic acidosis are characterized by episodes
of encephalopathy after ingestion of foods containing
The diagnosis of D-lactic acidosis is suspected in pa-
tients with disorders of the small intestine causing mal-
absorption and when the serum anion gap (Chapter 39)
is elevated in the presence of normal serum levels of
L-lactate and other organic acids. Measurement of serum
D-lactate requires special enzymatic procedures utilizing
D-lactate dehydrogenase and
D-lactate is con-
verted to pyruvate,
is oxidized to
which is
detected spectrophotometrically (Chapter 8).
The treatment of D-lactic acidosis consists of oral ad-
ministration of antibiotics, limitations of oral carbohydrate
intake, and recolonization of the colon by bacterial flora
which do not produce D-lactate.
Oxidation of Pyruvate to Acetyl-CoA
Pyruvate must first be transported into mitochondria by a
specific carrier that cotransports a proton to maintain elec-
trical neutrality. Inside mitochondria pyruvate undergoes
oxidative decarboxylation by three enzymes that function
sequentially and are present as a complex known as the
pyruvate dehydrogenase complex. The overall reaction
is physiologically irreversible, has a high negative AG°
(—8.0 kcal/mol, or —33.5 kJ/mol), and commits pyruvate
to the formation of acetyl-CoA:
Pyruvate + NAD+ + CoASH —>
acetyl-CoA + NADH + H+ + C 0
In the above reaction CoASH stands for coenzyme A
(Figure 13-7), and it contains the vitamin pantothenic
acid (Chapter 38). Coenzyme A functions as a carrier of
chapter 13
Carbohydrate Metabolism I: Glycolysis and TCA Cycle
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