Download GLYCOLYSIS AND GLUCONEOGENESIS

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GLYCOLYSIS AND
GLUCONEOGENESIS
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Glycolysis Function
Glycolysis Location
Glycolysis Connections
Glycolysis Regulation
Glycolysis ATP Yields
Glycolysis Equations
Effect of Arsenate
Lactate or Pyruvate
Gluconeogenesis Function
Gluconeogenesis Location
Gluconeogenesis Connections
Gluconeogenesis Regulation
Gluconeogenesis ATP Costs
Gluconeogenesis Equations
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(See Fig. 10-1.)
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ADP
GLYCOGEN
ATP
hexokinase
GLUCOSE
G6P
glucose-6-phosphatase
HMP Pathway
ATP
F6P
Pi
phosphofructokinase (PFK)
NADH
1,3-DPG
ADP
ATP
fructose-1,6-bisphosphatase
ADP F-1,6-P
2
NAD+
Pi
G3P
DHAP
glyceraldehyde-3
phosphate
dehydrogenase
LACTATE
3PGA
ADP
NAD+
lactate dehydrogenase
ATP
NADH
PEP
2PGA
PYRUVATE
pyruvate kinase
OAA
NADH
CO2
CO2
GDP + Pi
PEP carboxykinase
ATP
pyruvate carboxylase
GTP
ADP + Pi
NAD+
MALATE
MALATE
OAA
NAD+
NADH
MITOCHONDRIA
Figure 10-1
GLYCOLYSIS (solid lines) and GLUCONEOGENESIS (dotted lines) share
some common enzymes, but they diverge around the control steps. Major control enzymes are boxed. Signals that turn glycolysis on turn gluconeogenesis off,
and vice versa.
BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036
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Glycolysis and Gluconeogenesis
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GLYCOLYSIS FUNCTION
Aerobic: To convert glucose to pyruvate and ATP. Pyruvate can
be burned for energy (TCA) or converted to fat (fatty acid synthesis).
Anaerobic: ATP production. Recycle NADH by making lactate.
GLYCOLYSIS LOCATION
Cytosol of all cells.
GLYCOLYSIS CONNECTIONS
Glucose in, pyruvate or lactate out.
Glucose 6-phosphate to glycogen (reversible).
Glucose 6-phosphate to pentose phosphates (not reversible).
Pyruvate to TCA via acetyl-CoA (not reversible).
Pyruvate to fat via acetyl-CoA (not reversible).
GLYCOLYSIS REGULATION
Primary signals:
Insulin turns on.
Glucagon turns off.
Epinephrine turns on in muscle, off in liver.
Phosphorylation turns off in liver, on in
muscle.
Secondary signals: Glucose signals activate (fructose 2,6-bisphosphate activates phosphofructokinase).
Low-glucose signals inhibit.
High-energy signals inhibit.
Low-energy signals activate.
BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036
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GLYCOLYSIS ATP YIELDS
Aerobic:
Anaerobic:
Complete:
1 glucose ¡ 2ATP 2NADH 2 pyruvate
1 glucose ¡ 2ATP 2 lactate
1 glucose ¡ 6CO2 38ATP
(using malate/aspartate shuttle to oxidize NADH)
From glycogen: (Glycogen)n ¡ 3ATP 2NADH 2 pyruvate
GLYCOLYSIS EQUATIONS
Aerobic:
Glucose 2ADP 2Pi 2NAD ¡
2 pyruvate 2ATP 2NADH 2H
Anaerobic:
Glucose 2ADP 2Pi ¡ 2 lactate 2ATP
EFFECT OF ARSENATE
This is a common exam question.
Arsenate (HAsO2
4 ), an analog of phosphate, has an interesting
effect on glycolysis. This makes a great exam question. Arsenate is a substrate for the enzyme glyceraldehyde-3-phosphate dehydrogenase. The
enzyme, which normally uses phosphate and makes 1,3-disphosphoglycerate, is fooled by the arsenate and makes the arsenate ester instead. With
the phosphate ester, the next enzyme in glycolysis makes an ATP from
the 1,3-diphosphoglycerate. The arsenate analog of 1,3-disphosphoglycerate is chemically much more unstable than the phosphate ester and
hydrolyzes to 3-phosphoglycerate before an ATP can be made. The product, however, is the same—3-phosphoglycerate—so glycolysis can continue as normal. But what has happened is that this step no longer makes
an ATP for each three-carbon fragment. You lose 2 ATPs per glucose—
all the net ATP production of glycolysis. The bottom line is that glycolysis continues (in fact it’s usually accelerated by the lack of ATP), but
no ATP can be made. It is analogous to the uncoupling of oxidative phosphorylation by dinitrophenol.
BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036
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Glycolysis and Gluconeogenesis
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LACTATE OR PYRUVATE
With oxygen present, pyruvate is oxidized by the tricarboxylic acid
cycle (TCA).
Without oxygen, pyruvate is reduced to lactate.
In muscle, lactate is the usual product.
The product of glycolysis is pyruvate. The pyruvate made by glycolysis can either enter the TCA cycle through pyruvate dehydrogenase
or be reduced to lactate. To keep running, glycolysis requires NAD in
the glyceraldehyde-3-phosphate dehydrogenase reaction. No NAD, no
glycolysis. NAD is produced by oxidation of NADH via oxidative
phosphorylation, a process that requires oxygen. Under anaerobic conditions, the TCA cycle simply shuts down. The pyruvate is converted to
lactate to regenerate the NAD and keep glycolysis going. In muscle,
glycolysis is normally faster than the TCA cycle capacity, and lactate is
the usual product of glycolysis even in resting muscle. The lactate/pyruvate ratio is about 10 in resting muscle, but in working muscle this ratio
may hit 200.
GLUCONEOGENESIS FUNCTION
Gluconeogenesis makes glucose from pyruvate to help maintain
blood glucose levels.
GLUCONEOGENESIS LOCATION
Liver and kidney—not muscle.
GLUCONEOGENESIS CONNECTIONS
Pyruvate in, glucose out.
Lactate in, glucose out.
Alanine in, glucose and urea out.
Gluconeogenesis in the liver can be fueled by molecules other than
pyruvate or lactate. Alanine, a product of protein degradation, yields
pyruvate by simple transamination, and this pyruvate can be converted
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to glucose by the liver and kidney. Other amino acids are metabolized to
pyruvate or oxaloacetate, which can also enter the gluconeogenic pathway. In addition, glycerol from the breakdown of triglycerides in adipose
tissue can be used by the liver and kidney to make glucose.1
GLUCONEOGENESIS REGULATION
Primary signals:
Secondary signals:
Insulin turns off.
Glucagon turns on.
Acetyl-CoA turns on.
Phosphorylation turns on in liver.
Glucose signals turn off.
(Fructose 2,6-bisphosphate inhibits fructose
1,6-bisphosphatase.)
Low-glucose signals activate.
High-energy signals activate.
Low-energy signals inhibit.
There are two unusual aspects to the regulation of gluconeogenesis.
The first step in the reaction, the formation of oxaloacetate from pyruvate, requires the presence of acetyl-CoA. This is a check to make sure
that the TCA cycle is adequately fueled. If there’s not enough acetyl-CoA
around, the pyruvate is needed for energy and gluconeogenesis won’t
happen. However, if there’s sufficient acetyl-CoA, the pyruvate is shifted
toward the synthesis of glucose.
GLUCONEOGENESIS ATP COSTS
2 lactate 6ATP (equivalents) ¡ glucose
GLUCONEOGENESIS EQUATIONS
2 lactate 4ATP 2GTP ¡ glucose 4ADP 2GDP 6Pi
2 pyruvate 4ATP 2GTP 2NADH 2H ¡
4ADP 2GDP 6Pi 2NAD
1
The glycerol produced by the action of hormone-sensitive lipase in the adipose tissue cannot be utilized by adipose tissue itself. Adipose cells lack the enzyme glycerol kinase, which
is necessary to convert glycerol to glycerol phosphate.
BG McGraw-Hill: Gilbert, Basic Concepts in Biochemistry, JN 5036