SECTION 15.1
Gluconeogenesis
279
Glucose
t
Oxaloacetate
Cysteine
Alanine
Glycine
Hydro xyproline
Serine
Tryptophan
Tyrosine]
Phenylalanine!
Isoleucine
Methionine
Valine
Threonine
F I G U R E 1 5 -4
Points of entry of amino acids into the pathway of gluconeogenesis.
where B
6
-PO
4
= pyridoxal phosphate. An amino acid
is classified as ketogenic, glucogenic, or glucogenic/
ketogenic depending on whether feeding it to a starved
animal increases plasma concentrations of ketone bod-
ies (Chapter 18) or of glucose. Leucine and lysine
are purely ketogenic because they are catabolized to
acetyl-CoA, which cannot be used to synthesize glucose
(Chapter 17). Isoleucine, phenylalanine, tyrosine, and
tryptophan are both glucogenic and ketogenic, and the
remaining amino acids (including alanine) are glucogenic.
Entry points of the amino acids into the gluconeogenic
pathway are shown in Figure 15-4.
Glycerol
is more reduced than the other gluconeogenic
precursors, and it results primarily from triacylglycerol
hydrolysis in adipose tissue. In liver and kidney, glyc-
erol is converted to glycerol 3-phosphate by glycerol
kinase:
C H 2O H
Glycerol 3-phosphate is oxidized to dihydroxyacetone
phosphate by glycerol-3-phosphate dehydrogenase:
C H 2O H
I
C H O H
+ N A D +
----------------►
i
C H
2
O P 0 32 -
G ly cero l 3 - p h o s p h a te
C H 2O H
I
+
c=0
+ NADH + H +
C H
2
O P 0 32'
D ih y d ro x y a c e to n e p h o s p h a te
Dihydroxyacetone
phosphate
is
the
entry
point
of
glycerol into gluconeogenesis. Glycerol cannot be me-
tabolized in adipose tissue, which lacks glycerol kinase,
and the glycerol 3-phosphate required for triacylglyc-
erol synthesis in this tissue is derived from glucose
(Chapter 22). During fasting in a resting adult, about
210 mM of glycerol per day is released, most of which is
converted to glucose in the liver. During stress or exercise,
glycerol release is markedly increased (Chapter 22).
Propionate
is not a quantitatively significant gluco-
neogenic precursor in humans, but it is a major source
of glucose in ruminants. It is derived from the catabolism
of isolecucine, valine, methionine, and threonine; from
/3-oxidation of odd-chain fatty acids; and from the degra-
dation of the side chain of cholesterol. Propionate enters
gluconeogenesis via the TCA cycle after conversion to
succinyl-CoA (Chapter 18).
Regulation of Gluconeogenesis
Gluconeogenesis is regulated by the production and re-
lease of precursors and by the activation and inactiva-
tion of key enzymes. Glucagon and glucocorticoids stim-
ulate gluconeogenesis, whereas insulin suppresses it. See
Chapter 22 for a discussion of the overall metabolic control
and physiological implications of the several seemingly
competing pathways.
C H O H
+ A T P 4' ----------------»
I
C H 2O H
G ly cero l
C H 2O H
I
,
C H O H
+ A D P 3' + H
I
.
C H
2
0 P 0 32~
G ly cero l 3 - p h o s p h a te
Carboxylation o f Pyruvate to Oxaloacetate
The pyruvate carboxylase reaction is activated by Mg2+
and, through mass action, by an increase in either the
[ATP]/[ADP] or the [pyruvate]/[oxaloacetate] ratio. It
is virtually inactive in the absence of acetyl-CoA, an
allosteric activator. The enzyme is allosterically inhib-
ited by glutamate, since oxaloacetate formed in excess
would flood the TCA cycle and result in a buildup
of a-ketoglutarate and glutamate. Pyruvate carboxylase
