Download gluconeogenesis

KAPITOLA 8
Energetický metabolismus I
• glykolýza a kvašení
• pentózový cyklus
• glukoneogeneze
• lokalizace reakcí v buňce
• fyziologické aspekty bioenergetiky
Glycogen,
starch, sucrose
Major pathways of glucose utilization in
cells of higher plants and animals. Although
not the only possible fates for glucose, these
three pathways are the most significant in
terms of the amount of glucose that flows
through them in most cells.
Storage
Glucose
oxidation via
pentose phosphate
pathway
Ribose-5-phosphate
oxiadation via
glycolysis
Pyruvate
Three possible catbolic fates of the
pyruvate formed in the payoff phase of
glycolysis. Pyruvate also serves as a
precursor in many anabolic reactions, not
shown here.
•Primary metabolism of glucose
Glycolysis
The two phases of glycolysis.
For each molecule of glucose
that passes through the
preparatory phase (a), two
molecules of glyceraldehyde3-phosphate are formed; both
pass through the payoff phase
(b). Pyruvate is the end
product of the second phase
under aerobic conditions, but
under anaerobic conditions
pyruvate is reduced to lactate
to regenerate NAD+. For each
glucose molecule, two ATP
are consumed in the preparatory phase and four ATP are
produced in the payoff phase,
giving a net yield of two
molecules of ATP per one of
glucose converted to pyruvate. Keep in mind that each
phosphate group, represented
here as P, has two negative
charges (- PO32-).
Entry of glycogen, starch,
disaccharides, and hexoses
into the preparatory stage of
glycolysis.
Covalent
regulation
Allosteric
regulation
Covalent and allosteric regulation of
glycogen phosphorylase in muscle.
(a) The enzyme has two identical subunits, each
of which can be phosphorylated by
phosphorylase b kinase at Ser14 to give
phosphorylase a, a reaction promoted by
Ca2+. Phosphorylase a phosphatase, also
called phosphoprotein phosphatase-1, removes these phosphate groups, inactivating the
enzyme. Phosphorylase b can also be
activated by noncovalent binding of
AMP at its alosteric sites. Conformational
changes in the enzyme are indicated
schematically. Liver glycogen phosphorylase undergoes similar a and b interconversions, but has different regulatory mechanisms.
(b)
The three-dimensional structure of the
enzyme from muscle. The two subunits (gray
and blue) of the glycogen phosphorylase a
dimer, showing the location of the
phosphates (orange) attached to the Ser14
residues (red) in each..
In phosphorylase b, the amino-terminal peptide
containing Ser14 is disordered. However, with
the attachment of negatively charged
phosphate group at Ser14 this peptide folds
toward several nearby (positively charged)
Arg residues (pink), forcing compensatory
changes in regions distant from Ser14 and
activating the enzyme.
AMP, the allosteric activator of phosphorylase
b, binds very near Ser14. On the back side of
the enzyme is a deep channel that admits
the substrate glycogen to the active site,
which is 3,3 nm away from the allosteric
site.
(c) A close-up view of the region around the
phospho-Ser residue; note its proximity to the
interface between dimers.
Hormonal regulation of glycogen
phosphorylase in muscle and liver.
A cascade of enzymatic activations
leads to activation of glycogen
phosphorylase by epinephrine in
muscle and by glucagon in liver.
When catalysts activate catalysts
large amplifications of the initial
signal results.
• Secondary metabolism of glucose:
Pentose phosphate pathway
The oxidative reactions of the pentose
phosphate pathway, leading to D-ribose5-phosphate and producing NADPH.
The nonoxidative reactions of the pentose
phosphate pathway convert pentose phosphates
back into hexose phosphates, allowing the
oxidative reactions to continue. The enzymes
transaldolase and transketolase are specific to
this pathway; the oher enzymes also serve in the
glycolytic or gluconeogenetic pathways.
A simplified schematic diagram showing the
pathway leading from six pentoses (5C) to
five hexoses (6C).
Secondary pathways for glucose metabolism
through UDP-glucuronate.
Energy metabolism
(anabolism)
Gluconeogenesis
The pathway from phosphoenolpyruvate to glucose-6-phosphate
is common to the biosynthetic
conversion of many different
precursors into carbohydrates
in animals and plants.
bypass #1
Gluconeogenesis
bypass #2;3
The opposing pathways of glycolysis and
gluconeogenesis in rat liver. The three bypass
reactions of gluconeogenesis are shown in
orange. Two major sites of regulation of
gluconeogenesis are also shown.
Alternative paths from pyruvate
to phosphoenolpyruvate. The paths
differ depending upon the gluconeogenetic precursor (lactate or
pyruvate) and are determined by
cytosolic requirements for NADH
in gluconeogenesis.
Gluconeogenesis
bypass #1
Liver cells
Muscle cells
FA/ β – oxidation
Triacylglycerols stored in seeds are oxidized
to acetyl-CoA and dihydroxyacetone
phosphate during germination; both are
substrates for gluconeogenesis in plants. Recall
that acetyl-CoA is not a substrate for
gluconeogenesis in animals.
Glyoxylate cycle
The conversion of stored fatty acid to
sucrose in germinating seeds begins in
glyoxysomes, which produce succinate
and export it to mitochondria. There it
is converted to oxaloacetate by enzymes of the citric acid cycle.
Oxaloacetate enters the cytosol
and serves as the starting material
for gluconeogenesis and the
synthesis
of
succrose,
the
transported sugar in plants.
gluconeogenesis
FA/ β – oxidation
Triacylglycerols stored in seeds are oxidized
to acetyl-CoA and dihydroxyacetone
phosphate during germination; both are
substrates for gluconeogenesis in plants. Recall
that acetyl-CoA is not a substrate for
gluconeogenesis in animals.
Energy metabolism
(Anabolism)
Glycogenogenesis
The glycogen-branching enzyme glycosyl-(46)-transferase (or
amylo (14) to (1  6) transglycosylase) forms a new branch
point during glycogen synthesis.
The glycogen-branching enzyme glycosyl-(46)-transferase (or
amylo (14) to (1  6) transglycosylase) forms a new branch
point during glycogen synthesis.
!!!
Initiating the synthesis of a glycogen particle with a protein
primer, glycogenin. Steps 1 through 5 are described in the text.
Glycogenin is found within glycogen particles, still covalently
attached to the reducing end of the molecule.
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Energy metabolism
Gluconeogenesis