What is glycogenesis?
Creation of glycogen from glucose
Which 3 enzymes are used in glycogenesis?
Hexokinase/glucokinase
Phosphoglucomutase
Branching enzyme
Describe the process of glycogenesis
Glucose Glucose-6-phosphate Glucose-1-phosphate UDP-glucose Added to current glycogen stores
Describe the process of glycogenolysis
Glycogen store
Glucose-6-phosphate using phosphoglucomutase
Enters glycolysis and broken down by glucose-6-phosphatase
What is Von Gierke’s disease?
Glycogen storage disease. Absence of glucose-6-phosphatase
What is lipogenesis?
Process of creating long chain fatty acids using ATP and acetyl CoA
Which enzyme is used in lipogenesis?
Acetyl carboxylase
Which 2 compounds allosterically regulate lipogenesis?
Citrate –> increases
AMP –> decreases
What are the two main free oxide radicals?
Nitric oxide
Hydroxyl groups
Which two enzymes are responsible for removing/converting free oxide radicals?
Superoxide dismutase (SOD) Catalase
Which two forms of glutathione can be found in a cell?
GSH
GSSG
How does the free form of glutathione GSH become GSSH?
GSH donates a hydrogen ion and conjugates with another GSH molecule to form GSSG
Which molecule is responsible for converting GSSH back into GSH?
NADPH provides a hydrogen ion
Why may nitric oxide be produced naturally by the body?
It has potent vasodilator effects
Which molecule is nitric oxide formed from?
Arginine
Describe the process of insulin release from beta cells in the pancreas
Increased glucose uptake via GLUT2 channels causes an increase in ATP
ATP sensitive potassium channel closes
Increased K+ in the cell
Depolarises membrane so more Ca2+ enters cell
Insulin vesicles fuse with the cell membrane and insulin in released
Name the 3 layers of the cortex of the adrenals
Zona glomerulosa
Zona fasciculata
Zona reticularis
What is secreted from the zona glomerulosa?
Mineralocorticoids- eg. aldosterone
What is secreted from the zona fasciculata?
Glucocorticoids- eg. cortisol
What is secreted from the zona reticularis?
Androgens- eg. testosterone
Which layer lies superficially to the adrenal cortex?
Capsule
Which layer lies inferiorly to the adrenal cortex?
Medulla
What is secreted from the medulla?
Catecholamines- adrenaline and noradrenaline
Which cells secrete catecholamines in the medulla of the adrenal glands?
Chromaffin cells (by sympathetic stimulation)
What is the action of aldosterone?
Acts in the DVT to upregulate Na/K ATPase and increase expression of ENaC
What are the main actions of cortisol?
Stimulate gluconeogenesis
Breakdown proteins
Redistribute fat to become more centralised
Describe the HPA axis system involved in the release of cortisol from the adrenal glands
CRH released from the hypothalamus
ACTH released from the anterior pituitary
Cortisol secreted and feeds back negatively to the hypothalamus and pituitary
Give some examples of cushingoid signs
Dorso-cervical fat pad Muscle atrophy Hypertension Striae Weight gain Hyperpigmentation
Why does excess cortisol cause hyperpigmentation?
When POMC is broken down to produce ACTH, it also produces alpha-MSH which stimulates melanocytes
When are cortisol levels in the body highest?
In the morning
Where is the thyroid gland located?
Anterior trachea, inferior to cricoid cartilage
What structure separates the two lobes of the thyroid?
Isthmus
Which cells produce thyroid hormone?
Thyrocytes
What substance is found in high concentrations in the colloid?
Thyroglobulin
Which hormone is primarily secreted by the thyroid?
T4
Which hormone released from the thyroid is the most potent?
T3
Which thyroid hormone is most commonly found in the circulating system?
T3
Which 2 plasma proteins are mainly bound to thyroid hormones?
Albumin
Thyrotropin releasing hormone (TRH)
What hormone is released from the anterior pituitary to stimulate release from the thyroid hormone?
Thyroid stimulating hormone (TSH)
What ion is used in the production of thyroxine?
Iodine
How does iodine enter the thyrocytes?
Na/K-ATPase extrudes Na from the cell into the blood so iodine can use the Na gradient to move into the cell via the sodium-iodine symporter (NIS).
Where do iodine ions bind to thyroglobulin in the colloid?
Tyrosine residues
Which enzyme allows iodine to bind to thyroglobulin?
Thyroid peroxidase
What are the 4 functions of thyrocytes?
Uptake of iodine ions from the blood
Secretion of thyroglobulin into the colloid
Addition of iodine to the free tyrosine residues
Secretion of T4 and T3 into the blood
What is Grave’s disease?
Hyperthyroidism caused by a circulating antibody which stimulates excess thyroid hormone production
What is a goitre?
Enlarged neck due to thyroid disease
Give 3 symptoms of hyperthyroidism
Thinning hair Heat intolerance Irritability Nervousness Weight loss Palpitations
What is Hashimoto’s disease?
Hypothyroidism caused by autoimmune destruction of the thyroid gland
What can untreated hypothyroidism at birth cause?
Stunted growth
Delayed sexual development
Protruding tongue
Significant mental retardation
Which bone is the pituitary found in?
Sphenoid
What embryological derivative is the anterior pituitary derived from?
Infundibulum
What embryological derivative is the posterior pituitary derived from?
Rathke’s pouch
Which two hormones does the posterior pituitary release?
ADH
Oxytocin
Which hormones are secreted by the anterior pituitary?
LH FSH GH TSH ACTH Prolactin
What is Cushing’s disease?
Pituitary adenoma secreting excessive ACTH
What is Cushing’s syndrome?
Overactive adrenal glands secreting too much cortisol
From which structure can ectopic secretions of ACTH most commonly be secreted from?
(Paraneoplastic syndrome) Small cell lung carcinoma
Explain how a dexamethasone suppression test can identify the cause of hypercortisolism
Dexamethasone suppresses the pituitary gland’s ability to produce ACTH.
In Cushing’s disease ACTH levels will fall and therefore cortisol levels should also fall
In Cushing’s syndrome and ectopic ACTH secretion the levels of cortisol will remain high
What is pharmacokinetics?
What the body does to a drug
What is pharmacodynamics?
What the drug does to the body
What is phase I metabolism of a drug?
Oxidation, reduction or hydrolysis of the drug to convert it to the active form
What is phase II metabolism of a drug?
Conjugation of the drug so it becomes soluble and can be excreted
Give 3 ways a drug can be conjugated in phase II metabolism
Glucuronidation
Sulphate conjugation
Glutathione conjugation
Explain the metabolism of paracetamol at high concentrations
The normal metabolic pathways of paracetamol become saturated so it goes through a phase I pathway to become NAPQI. NAPQI builds up in the cells as the phase II metabolism (glutathione conjugation) is saturated. The NAPQI build-up causes toxic effects to the hepatocytes
What can be given to reverse the effects of paracetamol overdose?
N-acetyl cysteine
Explain the Phase I and Phase II metabolism of alcohol
Alcohol
Acetaldehyde via alcohol dehydrogenase
Acetic acid via aldehyde dehydrogenase
Which drug can be given to alcoholics to inhibit aldehyde dehydrogenase to give extreme hangovers?
Disulfiram
Give 3 important enzymes involved in glycolysis and the steps they are involved with
Hexokinase (step 1)
Phosphofructokinase (step 3)
Pyruvate kinase (step 10)
What is the action of hexokinase in glycolysis?
Breaks down glucose to glucose-6-phosphate
What does pyruvate kinase form in the final step of glycolysis?
Pyruvate and ATP
In the absence of oxygen what happens to pyruvate produced in glycolysis?
Converted to lactate by lactate dehydrogenase
What is the function of the pentose phosphate pathway?
Produce 5 carbon sugars used in DNA + RNA synthesis
Produce NAPDH
Explain the metabolism of the pentose phosphate pathway
Glucose-6-phosphate
Becomes pentose sugar using glucose-6-phosphate dehydrogenase (G6PD)
What is the effect of a deficiency in G6PD?
NADPH stores in the blood not regenerated resulting in disulphide bond formation in RBCs
GSH remains in its GSSG form and produces Heinz bodies
This results in haemolytic anaemia
What enzyme is responsible for the breakdown of pyruvate in the Kreb’s cycle?
What does it form?
Pyruvate dehydrogenase
Forms acetyl Co-A
How does the acetyl Co-A enter the mitochondria?
Carnitine shuttle
What is gained from 1 rotation of the Kreb’s cycle?
3 NADH
1 FADH2
2 CO2
Describe the process of the electron transport chain
NADH and FADH2 release electrons into the ECT and become oxidised.
The electrons move down the chain and pump H+ ions into the intermembrane space
The electrons bind to hydrogen and oxygen to form water at the end of the chain
The high H+ concentration in the intermembrane space flows back into the matrix via ATPsynthase which produces ATP.
What substance is produced from brown adipose tissue and what action does it have on the ECT?
Thermogenin
Uncouples the ECT from ATPsynthase to release heat instead of ATP
Give the 4 types of lipoprotein
Chylomicrons
VLDLs
LDLs
HDLs
Where/ and in what cell are chylomicrons produced?
Intestine- enterocytes
How do chylomicrons reach the systemic circulation?
Transfer through lacteal (intestinal) lymphatic system and enter into the left subclavian vein
Where are LDLs formed?
Liver
Which apoprotein is expressed on the surface of LDLs?
B100
Where are HDLs produced?
Tissues
How are levels of cholesterol assessed in the blood?
HDL/LDL ratio
How do fats normally circulate in the blood?
TAGs (triacylglycerols)
What is a TAG made up of?
Glycerol backbone
3 fatty acid chains
What is lipolysis?
Breakdown of TAGs
How can fatty acids enter the mitochondria?
Activated by acetyl Co-A and moved through the carnitine shuttle
Describe the process of beta oxidation of fatty acids
Series of oxidation reactions by FAD and NAD occur in the mitochondrial matrix.
Each oxidation reaction produces a molecule of acetyl Co-A and a fatty acid chain 2 carbons shorter than previously
Describe the metabolsim of an acetyl Co-A molecule to form a ketone body
Acetyl Co-A
HMG
(using HMG CoA reductase)
Ketone bodies
What is the body’s main source of nitrogen?
Amino acids from dietary protein
How is the toxic nitrogen (in the amine group of an amino acid) neutralised in the body?
Transamination- adding amine group to another molecule
Deamination- removal of amine group to form ammonia
Which enzymes are used in transamination?
ALT- alanine aminotransferase
AST- aspartate aminotransferase
How is urea produced in the body?
Ammonia or glutamate enter the urea cycle
Converted to arginine
Arginine broken down into urea and ornithine
What happens to the urea and ornithine produced in the urea cycle?
Urea excreted in the urine
Ornithine recycled
What is refeeding syndrome?
Chronic lack of food causes depression of the urea cycle as nitrogen levels are low
Sudden excess protein causes build up of nitrogen as urea cycle cannot cope with the sudden influx.
Ammonia accumulates in the blood and causes toxicity
What structure regulates appetite?
Arcuate nucleus in the hypothalamus
Explain the process of stimulating appetite
Primary fibres secrete neuropeptide Y
Secondary fibres cause hypothalamus to secrete Ghrelin
Explain the process of inhibiting appetite
Primary fibres secrete POMC
Secondary fibres cause hypothalamus to secrete PYY
Where is leptin secreted from?
Adipocytes
What is the action of leptin?
Works on arcuate nucleus to secrete inhibitory hormones to suppress appetite
What is galactosaemia?
Galactose cannot be metabolised
Explain the normal metabolism of galactose
Galactose
Galactose-1-phosphate (via galactokinase)
UDP-galactose (via galactose-1-phosphate uridyl transferase)
Which enzyme is more commonly affected in galactosaemia?
G1P uridyl transferase
In galactosaemia, how is galactose metabolised?
Galactose becomes galactitol via aldose reductase- uses NADPH
Why do patients with galactosaemia present with cataracts?
NADPH stores diminished
Disulfide bonds form and patient at higher risk of ROS attack
Proteins aggregate in the eye causing cataracts
What is phenylketonuria?
Deficiency in phenylalanine hydroxylase enzyme
Usually converts phenylalanine to tyrosine
What abnormal metabolism occurs in phenylketonuria?
Phenylalanine is converted to phenylpyruate which is excreted in the urine
Why do patients with phenylketonuria suffer from mental retardation?
Excessive phenylalanine blocks non-specific amino acid tranporters at the BBB so essential amino acids cannot work to provide normal CNS development
What is homocystinuria?
Deficiency in cystathione beta synthase (CBS) enxyme.
It is normally used to breakdown homocysteine to cystathionine which is then converted to cysteine
In homocystinuria, what happens to the excess homocysteine?
Some converted to methionine
Excreted in urine