Protein metabolism and gluconeogenesis (maam’s
slides)
Transamination = transfer of amino acid amine to an
alpha - keto acid
- Once free amino acids are made (by
proteasomes, pepsin, trypsin) and transported in
the bloodstream, they are transaminated in the
cell to yield a different alpha - keto acid and a
different amino acid.
- The goal is to get to glutamate, which can be
deaminated, and the resulting nitrogen excreted
safely.
Oxidative deamination
- Removes the amino group as an ammonium ion
from glutamate
- Provides alpha - ketoglutarate for transamination
Glutamate dehydrogenase deaminates glutamate
- Activated by ADP and NAD+
- Inhibited by NADH
- The ammonium ion liberated is eventually
excreted through the urea cycle
Fate of the carbon skeletons
- The amine enters the urea cycle, and the
nitrogen eventually excreted.
- The rest of the acid skeleton is recycled in a
number of ways. (ketogenic at glucogenic. See
picture and table)
- Carbon skeletons are used for energy.
- Glucogenic: TCA cycle intermediates or
pyruvate (gluconeogenesis)
- Ketogenic: acetyl CoA, acetoacetyl CoA, or
acetoacetate
The urea cycle
- Detoxifies ammonium ion from amino acid
degradation
- Converts ammonium ion to urea in the liver
- Provides 25-30 g urea daily for urine formation
in the kidneys
*production of NH4+ and its release from the muscle are
proportional to intensity of exercise
Regulation of protein turnover
- The protein ubiquitin is used to mark cellular
proteins for destruction
- Hormone that promote,
- Synthesis: insulin
- Breakdown: cortisol
2+
- Ca concentration
Hormones that promote synthesis:
- Insulin
- IGG (insulin-like growth factor)
- Growth hormone
- Testosterone
Primary hormone for that promotes protein degradation
during starvation and exercise
- Cortisol
Degradation summary
- Amino acids are cleaved from the polypeptide
chain (protein molecule)
- Amino group is removed from the amino acid
- Through transamination and
deamination (glutamate formation and
alpha - ketoglutarate) - detoxification of
ammonium through urea cycle
- Carbon skeleton are
- Oxidized directly to generate energy
thru - CAC intermediates
- Oxidized thru acetyl CoA as ketone
bodies
- Converted to glucose thru
gluconeogenesis (liver) and later
oxidation
- Conversion into fat which can be stored
and then oxidized later
- Liver deaminates most amino acids
- Skeletal muscle has a great capacity of
BCAA
- Valine and isoleucine carbon
skeleton are converted to
succinyl CoA and enters the
CAC (glucogenic)
- Leucine carbon skeleton is
converted to acetoacetate
(ketogenic)
Importance of gluconeogenesis
- Provides glucose for the brain
- Clears lactate in the muscle
- Helps regulate blood glucose levels
Glucose is an indispensable metabolite
- The brain requires its energy source in the form
of glucose
- Red blood cells exclusively subsist on glucose
- Glucose is a precursor of other sugars needed
in the biosynthesis of nucleotides, glycoproteins,
and glycolipids
- Glucose is the preferred source of energy for
exercise
Liver is the major source of blood glucose from
gluconeogenesis
- Gluconeogenesis occurs mainly in the liver
- Gluconeogenesis occurs to a more limited
extent in kidney and small intestine
- Uses many small metabolites and fatty acids to
feed GN
- Liver function is highly sensitive to insulin and
glucagon
 - Synthesis of glucose from pyruvate utilizes
many of the same enzymes as glycolysis
- Three glycolysis reaction are essentially
nonreversible
- Hexokinase
- Phosphofructokinase
- Pyruvate kinase
These steps must be bypassed in
Gluconeogenesis
Bypassed
Glycolysis
- Hexokinase
- Phosphofructokinase -1
- Pyruvate kinase
*these enzymes are inhibited in
Gluconeogenesis so that glycolysis
Does Not occur
Gluconeogenesis counterpart
- Glucose-6-phosphatase
- Fructose 1,6-bisphosphate
- Pyruvate carboxylase and phosphoenolpyruvate
carboxykinase
Gluconeogenesis
- Substances that can become glucose
- Glucogenic amino acids
- Lactate, pyruvate
- Glycerol from triglycerides
- Krebs cycle intermediates
- Propionate from odd no ffa
Muscle proteins may break down to supply amino acids
- Transported to liver where they are deaminated
and converted to gluconeogenesis inputs
- The source of pyruvate and oxaloacetate for
gluconeogenesis during fasting or carbohydrate
starvation is mainly amino acid catabolism
- THUS amino acids are catabolized to pyruvate,
oxaloacetate, or precursors of these. CAC
intermediates and acetyl CoA
*all amino acids can feed into gluconeogenesis except
leucine and lysine
Gluconeogenesis from stored fats
Glycerol
- From lipolysis of triacylglycerols in fat cells,
gives a significant input to gluconeogenesis
- Provides 15% - 25% of the glucose produced by
the liver during starvation
- Propionate - 3 carbon leftover from fatty acids
can be converted to CAC intermediate succinyl
CoA
Lactate clearing
- Recall that vigorous exercise can lead to a
buildup of lactate due to oxygen shortage and
the need for more glycolysis
- Lactate is then returned to the liver, where it can
be oxidized to pyruvate by liver LDH
- Liver produces glucose to muscle for exercise
and then reprocesses lactate into new glucose
thru the cori cycle
- Cori cycle operates during exercise
Alanine cycle
- The liver can also use the amino acid alanine
similar to lactate
- Following transamination to pyruvate,
gluconeogenesis allows the liver to convert
alanine to glucose for secretion into the blood
Regulation of gluconeogenesis
- The regulated steps of glycolysis are the very
steps that are regulated in the reverse direction
(hexokinase, PFK, pyruvate kinase)
- Stimulated during low carbohydrate/glycogen
- Stimulated during fasting states, low-carb diets,
and severe exercise, high-blood/muscle lactate
accumulation
Hormones
Effects of glucagon in liver
- Gluconeogenesis is stimulated
- Glycogen breakdown is stimulated
- Glycogen synthesis is inhibited
- Free glucose is formed for release to the blood
Cortisol
- Stimulates protein breakdown in skeletal
muscle, amino acids for GN
- Stimulates gluconeogenic enzymes in the liver