Major Biochemical
Pathways
Activity 5
Introduction
•
Metabolism is the term used to describe
– The interconversion of chemical compounds in the
body
– The pathways taken by individual molecules,
– Their interrelationships, and the mechanisms that
regulate the flow of metabolites through the pathways
• It falls mainly in 3 categories: catabolism,
anabolism and amphibolic pathways
Metabolism
• Anabolic pathways
– Involved in the synthesis of larger and more
complex compounds from smaller precursors
– Ex: Synthesis of protein from amino acids and the
synthesis of reserves of tri-acylglycerol and
glycogen.
– Anabolic pathways are endothermic.
Metabolism
• Catabolic pathways
– Involved in the breakdown of larger
molecules, commonly involving oxidative
reactions;
– They are exothermic, producing reducing
equivalents, and, mainly via the
respiratory chain
Metabolism
• Amphibolic pathways
–Occur at the “crossroads” of
metabolism, acting as links
between the anabolic and
catabolic pathways
– Ex: Citric acid cycle
Metabolism
• A 70-kg adult human being requires about 1920-2900 kcal from
metabolic fuels each day, depending on physical activity.
• This energy requirement is met from
– Carbohydrates (40%-60%)
– Lipids (mainly triacylglycerol, 30%-40%)
– Protein (10%-15%), as well as alcohol.
• There is a constant requirement for metabolic fuels throughout
the day
• Most people consume their daily intake of metabolic fuels in
two or three meals, so there is a need to form reserves
Metabolism
• Reserves of
– Carbohydrate: glycogen in liver and muscle
– Lipid: triacylglycerol in adipose tissue
– Labile protein •
• If the intake of metabolic fuels is consistently greater than energy
expenditure.
– Surplus is stored, largely as triacylglycerol in adipose tissue,
– Leading to the development of obesity
• If the intake of metabolic fuels is consistently lower than energy
expenditure
– Reserves of fat and carbohydrate, and amino acids are used for energyyielding metabolism
– This leads to emaciation, wasting, and, eventually, death
Metabolism
• All the products of digestion are
metabolized to acetyl-CoA - oxidized
by the citric acid cycle
Carbohydrate Metabolism
• Carbohydrates function
– Major energy source for sustainment of life
(storage & generation)
– Cell wall of bacteria & aid in molecular
recognition and communication.
– Such as blood group sugars on cell surface •
Major disease is Diabetes Mellitus
Glucose Metabolism
▪ During a fast, the blood glucose level is kept
constant by mobilizing the glycogen stores in the
liver.
▪ During long fasts, gluconeogenesis is required to
maintain blood glucose levels because glycogen
stores are used up in about 24-48 hours.
▪ An individual with a fasting blood glucose level >100
mg/dL is referred to as hyperglycemic.
▪ An individual with a fasting blood glucose level <50
mg/dL is referred to as hypoglycemic. update
Major biochemical pathways
• Glycolysis
– is a cytoplasmic pathway which breaks down glucose
into two three-carbon compounds and generates
energy.
– Phosphorylation pf CHO-hexokinase
– Use of ATP
– Glycolysis is used by all cells in the body for energy
generation.
– final product of glycolysis is pyruvate in aerobic
settings and lactate in anaerobic conditions.
Major biochemical pathways
• Glycogenesis
–
–
–
–
Glycogen synthesis
important in liver and muscle
is an anabolic process that requires energy.
Glycogen- primary carbohydrate stored in the liver
and muscle cells of animals, from glucose.
– takes place when blood glucose levels are sufficiently
high
– is the process of storing excess glucose for use by
the body at a later time.
Major biochemical pathways
• Tricarboxylic Acid
–
–
–
–
also called Krebs cycle and citric acid cycle
the second stage of cellular respiration
Carried out in the intracellular structure-mitochondria
plays a central role in the breakdown, or catabolism,
of organic fuel molecules-glucose; other sugars, fatty
acids and some amino acids
Before these rather large molecules can enter the TCA cycle they must
be degraded into a two-carbon compound called acetyl coenzyme A
(acetyl CoA). Once fed into the TCA cycle, acetyl CoA is converted
into carbon dioxide and energy.
Major biochemical pathways
• Pentose Phosphate Pathways
– Also known as hexose monophosphate shunt
– fundamental component of cellular metabolism.
– parallel to the glycolysis pathway and takes place in
the cytoplasm
– used to produce ribose-5-phosphate and nicotinamide
adenine dinucleotide phosphate (NADPH)
⮚ribose-5-phosphate- precursor for the synthesis of
nucleotides and nucleic acids.
⮚NADPH- is an essential electron donor in all organisms,
and provides the reducing power for anabolic reactions and
redox balance
Major biochemical pathways
• Pentose Phosphate Pathways
– plays a critical role in regulating cancer cell growth by
supplying cells with not only ribose-5-phosphate but
also NADPH for detoxification of intracellular reactive
oxygen species, reductive biosynthesis,
and ribose biogenesis.
Major biochemical pathways
• Glycogenolysis
– process by which glycogen is broken down
into glucose to provide immediate energy and to
maintain blood glucose levels during fasting
– occurs primarily in the liver and is stimulated by the
hormones glucagon and epinephrine (adrenaline).
Major biochemical pathways
• Gluconeogenesis
– occurs in the liver and kidneys.
– supplies the needs for plasma glucose between
meals.
– stimulated by the diabetogenic hormones (glucagon,
growth hormone, epinephrine, and cortisol).
– helps to maintain the glucose level in the blood so
that brain and muscle can extract sufficient glucose
from it to meet their metabolic demands.
Metabolic pathways
Glycolysis
-------
Glucose
Pyruvate
Glycogenesis
-------
Glucose
glycogen
Tricaboxylic acid cycle ------- Glucose
+ATP
pyruvate
Pentose Phosphate Pathways ----- Glucose
Glycogenolysis ------------ Glycogen
Lactate
Co2+H20
ribose+CO2+NADPH
glucose
Gluconeogenesis --------- Non carbohydrates sou rce, protein, fats
glucose
Hormonal control and major site of
glucose regulation
– Islets of Langerhans in the pancreas prodce
1. Alpha cells secrets glucagon
2. Beta cells secretes insulin
3. Delta cells-somatostin
Normal Blood Glucose
• Fasting blood glucose- 20-105 mg/dL
• May rise to 130-160 mg/dL about 1 hr after a
glucose load or after high carbohydrate meal
(postprandial). • After 2 hr, it drops back to
normal fasting range
Hormones Affecting Blood
Glucose Levels
•
•
•
•
•
•
•
•
Insulin
Glucagon
Epinephrine
Growth hormone
Adreno-corticotropic hormone ACTH
cortisol
Somatostatin
T3 &T4
Insulin (hormone)
• Secreted by pancreas B cells of islets of
Langerhans.
• Primary function is to decrease blood
glucose & movement of glucose from
blood into cells.
Insulin (hormone)
• Actions:
– Facilitate the entry of glucose into hepatocyte, adipocytes,red
cells and monocytes by making the cell membrane permeabile to
glucose.
– Increases uptake of glucose by liver promotes glycogenesis and
lipogenesis.
– inhibits hepatic output of glucose into circulation
– increases synthesis of protein in the liver, muscle and fat cells.
– decreases gluconeogenesis.
So insulin reduces plasma glucose
So insulin work to return the glucose level back to normal
by lowering it and facilitatesits entry into the cells.
Glucagon (hormone)
• Secreted by α cells of islets, secretion is
regulated by plasma glucose concentration.
Insulin inhibits glucagon release.
• Primary function:
– increases blood glucose conc and FFA,
mobilization of energy stores.
• Actions:
– stimulates breakdown of liver glycogen into
glucose (Glycogenolysis)
– increase liver gluconeogenesis (from non carb) promotes hepatic lipolysis.
Epinephrine (hormone)
• Secreted by adrenal medulla
• Primary function: increases blood glucose and
mobilize energy stores.
• Actions:
–
–
–
–
Increases glycogenolysis
Stimulates glucagon secretion - Inhibits insulin secretion
Increase TG breakdown in adipose tissue (lipolysis).
Physical or emotional stress causes increased secretion of
epinephrine and an immediate increase in blood glucose levels.
Growth Hormone
• Polypeptide secreted by the anterior pituitary •
• Primary action: increase in blood glucose and
mobilize energy stores.
• Actions:
– increases gluconeogenesis
– antagonizes insulin
– inhibits lipogenesis from carbohydrates
Adreno-corticotropic
hormone ACTH
• Secreted by anterior pituitary
• Primary function: increases blood glucose &
and mobilize energy stores.
• Actions: - antagonizes insulin
Cortisol
• Secreted by adrenal cortex
• Primary function: increases blood glucose & and
mobilize energy stores.
• Actions:
–
–
–
–
Promotes protein catabolism
Promotes deamination of amino acids
Promotes gluconeogenesis
Inhibits glucose metabolism in the peripheral
tissues – antagonist of insulin.
Thyroid hormones T4 & T3
• Secreted by the thyroid gland
• Primary function: increases blood glucose & and
mobilize energy stores.
• Actions:
– stimulates glycogenolysis
– increases intestinal absorption of glucose
– accelerates the degradation of insulin.
Somatostatin
• Peptide hormone synthesized by delta by the
alpha cells of the pancreatic islets of
Langerhans.
• Inhibits both insulin, glucagon and growth
hormone release , resulting in an increase in
plasma glucose level
Hormones
• So Glucagon Epinephrine Growth hormone
ACTH Cortisol T3 & T4 Increases blood glucose
& and mobilizes energy stores.
• So which hormone increase in
Hypoglycaemia???
ABNORMALITIES IN
CARBOHYDRATES
METABOLISM
Lactose Intolerance
• Lactose or milk sugar found in the milk of
mammals - 4-6% in cow's milk and 5-8% in
human milk.
– It is also a by product in the manufacture of
cheese.
• Lactose intolerance is the inability to digest
significant amounts of lactose, the predominant
sugar of milk
Lactose Intolerance
• This inability results from a shortage of the
enzyme lactase, which is normally produced by
the cells that line the small intestine.
• Lactase breaks down the lactose, milk sugar,
into glucose and galactose that can then be
absorbed into the bloodstream.
Lactose Intolerance cont’d
• Common symptoms (sever to mild) include: o
–
–
–
–
–
–
abdominal pain
abdominal bloating
Gas
diarrhea
nausea
uncomfortable 30 minutes to 2 hours after
consuming milk and milk products
• Diagnostic Test
– Hydrogen Breath Test.
– Stool AcidityTest.
Hypoglycemia
• fasting blood glucose < 70 mg/d
• the body respond by secreting glucagon and
epinephrine
• Causes of hypoglycemia
• starvation
• exaggerated insulin release -hyperinsulinemia,
• •Over administration of insulin or oral
hypoglycemic agents
• Sever hepatic dysfunction
Hypoglycemia
• Fasting blood levels < 50 mg/dL uncommon.
• Rapid drop in blood glucose (< 50 -55 mg/dL)
will cause release of epinephrine leading to:
– in early stage: anxiety, dizziness, chills,
tachycardia and increase perspiration.
• Blood levels < 20 mg/dL (later stages) lead to:
– impaired nerve function & nerve damage, slurred
speech, loss of motor coordination, coma,
lethargy, confusion, seizures
Hyperglycemia
• Remember: normal fasting blood glucose 70 to
105 mg/dL
• Hyperglycemia - fasting blood glucose > 105
mg/dL.
• Diabetes mellitus - a disorder in glucose
metabolism producing hyperglycemia. •
• Remember: hypoglycemia - fasting blood
glucose < 70 mg/dL
Diabetes Mellitus
• commonly known as diabetes
• metabolic disease that causes high blood
sugar.
• Untreated high blood sugar from diabetes can
damage your nerves, eyes, kidneys, and other
organs.
Diabetes Mellitus
• There are a few different types of diabetes
– Type 1 diabetes is an autoimmune disease. The immune system
attacks and destroys cells in the pancreas, where insulin is
made.
– Type 2 diabetes occurs when your body becomes resistant
to insulin, and sugar builds up in your blood.
– Prediabetes occurs when your blood sugar is higher than
normal, but it’s not high enough for a diagnosis of type 2
diabetes.
– Gestational diabetes is high blood sugar during pregnancy.
Insulin-blocking hormones produced by the placenta cause this
type of diabetes.
Diabetes Mellitus
•
General symptoms
– increased hunger
– increased thirst
– weight loss
– Frequent urination
– Blurry vision
– Extreme fatigue
– Sores that don’t
heal
men with diabetes may have a decreased sex
drive, erectile dysfunction (ED), and poor
muscle strength.
Women with diabetes can also have symptoms
such as urinary tract infections, yeast
infections, and dry, itchy skin.
Diabetes Mellitus
• Causes
– Decrease or absence of nsulin secretion
– Insulin resistance
– Abnormality in the control of insulin
secretion
– Insulin action defect on target cell
Glycogen Storage Disease (GSD)
• GSD are group of inherited inborn errors of
metabolism due to deficiency or dysfunction
of the of enzymes
• Confined just to liver and muscles
• But some cause more generalised
pathology and afect tissue such as kidney,
heart and bowel
• The classification of GSD is based on the
enzyme deficiency and the affected tissue
Glycogen Storage Disease (GSD)
• Type 1 –Von Gierke’s Disease
– Affected enZyme-glucose 6 phosphatase
– Affected Tissue-liver and kidney
– Large quantities of glycogen are formed and
stored in hepatocytes, renal and intestinal
mucosa cells. The liver and kidneys become
enlarged
Glycogen Storage Disease (GSD)
• Type II-Pompe’sDisease
– Deficiency of enzyme alpha 1, 4 glucosidase
(acid malatase) lead to accumulation of glycogen
in many tissues
– In infantile form accumulation of glycogen in
cardiac muscles lead to cardiac failure
– liver-hepatomegaly and elevation of hepatic
enzymes
– Muscle and peripheral nerves-hypotonia and
weakness
– Blood vessels-intracranial aneurysms
Glycogen Storage Disease (GSD)
• Type III-Cori Disease
– Enzyme-flycogen debranching enzyme
– Affected Tissue-liver and muscle
– Can lead to liver cirrhosis and hepatocelular carcinoma
▪
▪
▪
▪
▪
Type IV-Andersen’s Disease; Amylopectinoses
Enzyme-gycogen debranching enzyme
Affected Tissue-Many including liver
Treatment: liver transplant
Mostly death by age 4 due to cirrhosis and portal
hypertension
Glycogen Storage Disease (GSD)
• Type V Mac Ardles disease
–
–
–
–
Myophophorylase deficiency
Affect muscle
Eraly life-muscle strength and reflexes may be normal
Later adult life-persistent proxmal weakness and muscle
wasting
• Type VI- Hers Disease
– Liver phosphorylase enzyme deficiency
– Affect liver, rare in cardiac form
– Hepatomegaly, hypoglycemia, growth retardatio,
hyperlipidemia
Glycogen Storage Disease (GSD)
• Type VII Tarui disease
– Phosphofructokinase deficiency
– Musle is affected
– Exercise intolerance, msucle cramping
• Type VIII-Fanconi-Bickel syndrome
– Glucose transporter GLUT 2
– Similar feature to Von Gierke’s disease
Glycogen Storage Disease (GSD)
• Type 0 Lewis diesease
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–
–
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Hepatic Glycogen synthase
Affects lives
Fatigue and muscle cramps after exertion
Mild growth retardation in some case
• Type VI- Hers Disease
– Liver phosphorylase enzyme deficiency
– Affect liver, rare in cardiac form
– Hepatomegaly, hypoglycemia, growth retardatio,
hyperlipidemia
References
• https://www.slideshare.net/DeepakKumarGu
pta2/metabolism-50519317
• https://www.slideshare.net/promotemedical/g
lycogen-storage-disease-gsd