section 13.2
Pyruvate Metabolism
235
triacylglycerol enters the glycolytic pathway by way of
dihydroxy acetone phosphate, as follows:
glycerol kinase, M g2+
Glycerol + ATP4 - --------------------
>
glycerol 3-phosphate2-
+ ADP3- + H+
glycerol-3-phosphate dehydrogenase
Glycerol 3-phosphate2- + NAD+
<
........
—
>
dihydroxyacetone phosphate2- + NADH + H+
Role of Anaerobic Glycolysis in Various
Tissues and Cells
In tissues that lack mitochondria or function under limiting
conditions of oxygen (e.g., lens and erythrocytes), glycol-
ysis is the predominant pathway providing ATP. On the ba-
sis of speed of contraction and metabolic properties, skele-
tal muscle fibers may be classified into three types: type I
(slow-twitch, oxidative), type IIA (fast-twitch, oxidative-
glycolytic), and type IIB (fast-twitch, glycolytic). Short-
term, sudden energy output is derived from glycolytic
fibers. The glycolytic fibers (particularly type IIB) have
few mitochondria, with relative enrichment of myofibrils
and poor capillary blood supply. Thus, these fibers can
perform a large amount of work in a short period of time,
in contrast to slow-twitch fibers, which are rich in mito-
chondria, have good capillary blood supply, and power
sustained efforts (Chapter 21).
A high rate of glycolysis also occurs in lymphocytes,
kidney medulla, skin, and fetal and neonatal tissues. The
anaerobic capacity of lymphocytes is increased for growth
and cell division. Kidney medulla (Chapter 39), which
contains the loops of Henle and collecting tubules, receives
much less blood than the cortex and is rich in glycogen.
In contrast, kidney cortex, which contains the glomeruli,
proximal tubules, and parts of the distal tubules, receives
a large amount of blood through the renal arterioles. The
renal cortex derives its energy from oxidation of glucose,
fatty acids, ketone bodies, or glutamine to CO
2
and H
2
O.
Some rapidly growing tumor cells exhibit a high rate
of glycolysis. Inadequate oxygen supply (hypoxia) causes
tumor cells to grow more rapidly than the formation of
blood vessels that supply oxygen. Thus, in hypoxic tu-
mor cells, glycolysis is promoted by increased expression
of glucose transporters and most glycolytic enzymes by
hypoxia-inducible transcription factor (HIF-1).
Glycolytic Enzyme Deficiencies in Erythrocytes
The only pathway that provides ATP in mature ery-
throcytes is glycolysis. Because these cells lack mito-
chondria, a nucleus, and other organelles required for
protein synthesis, deficiency of glycolytic enzymes may
reduce their normal 120-day life span. For example,
deficiency of hexokinase, glucose-phosphate isomerase,
6
-phosphofructokinase, aldolase, triose-phosphate iso-
merase, or phosphoglycerate kinase is associated with
hemolytic anemia, whereas lactate dehydrogenase defi-
ciency is not. The most common deficiency is that of
pyruvate kinase, (PK), which is inherited as an autosomal
recessive trait. The PK deficiency occurs worldwide, how-
ever, it is most commonly found in kindreds of Northern
European ancestry. Erythrocyts of PK individuals have el-
evated levels of 2.3-DPG and decreased ATP level. Several
mutations of the PK gene have been identified. Individuals
with PK deficiency suffer from lifelong chronic hemolysis
to a varying degree. Splenectomy ameliorates hemolytic
process in severe cases.
Some enzymopathies of erythrocytes may be associ-
ated with multisystem disease (e.g., aldolase deficiency
with mental and growth retardation). Individuals with
6
-phosphofructokinase deficiency exhibit hemolysis and
myopathy and have increased deposition of muscle glyco-
gen (a glycogen storage disease; see Chapter 15). The my-
opathy is usually characterized by muscle weakness and
exercise intolerance. (See also Chapters 10, 15, and 28.)
13.2 Pyruvate Metabolism
Pyruvate has several metabolic fates. It can be reduced
to lactate, converted to oxaloacetate in a reaction impor-
tant in gluconeogenesis (Chapter 15) and in an anaplerotic
reaction of the TCA cycle (see below), transminated to ala-
nine (Chapter 17), or converted to acetyl-CoA and CO
2
.
Acetyl-CoA is utilized in fatty acid synthesis, cholesterol
(and steroid) synthesis, acetylcholine synthesis, and the
TCA cycle (Figure 13-6).
ALANINE
GLUCOSE
PYRUVATE
,
_____ [TntTI
► LACTATE
^
/
c r ^
fpci
/
I
ppm
/
\
OXALOACETATE
ACETYL CoA —► Fatty acids
I
I
Gluconeogenesis
^
TCA cycle
I
I
GLUCOSE
C0
2
+ H20
FIGURE 13-6
Major pathways of pyruvate metabolism. Pyruvate is metabolized through
four major enzyme pathways: Lactate dehydrogenase (LDH), pyruvate
dehydrogenase complex (PDH), pyruvate carboxylase (PC), and alanine
aminotransferase (ALT). Arrows indicate multiple steps.
