Metabolic Disorders Flashcards
What metabolic pathways oppose each other?
Glycolysis and gluconeogenesis
Beta oxidation and fatty acid synthesis
What must happen before triacyl glycerols can be used for metabolism?
They must by hydrolysed by lipases to release FA and glycerol
What are the 3 phases of fatty acid catabolism?
1) Activation of fatty acids (occurs in the cytosol)
2) Transport activated FA into mitochondria
3) Beta oxidation
What is the product of fatty acid catabolism?
Acetyl CoA
What happens during beta oxidation?
Successive removal of 2C units
Where does beta oxidation take place?
In the mitochondria
Where does stage 1 of fatty acid catabolism take place?
ER or cytosolic side of outer mitochondrial membrane
What happens in stage 1 of FA catabolism?
Fatty acid + HS-CoA + ATP -> Fatty acyl-CoA + H2O + AMP + PPi
What happens during phase 2 of fatty acid catabolism?
FA is transported to matrix of the mitochondria via carnitine
What happens to fatty acyl-CoA in stage 3 of fatty acid catabolism?
Beta oxidation. In this process acetyl CoA is formed which takes 2 carbons per cycle from the fatty acid.
A FADH2 and an NADH are gained every cycle.
14 carbon fatty acid would form 7 acetyl CoAs.
What happens if carnitine transport is defective?
Variability associated with hepatomegaly, liver disease, hypertrophic cardiomyopathy and potential arrhythmia.
Mild recurrent muscle cramping - severe weakness - death
What are the 2 different kinds of carnitine metabolism disorders?
Primary: Low carnitine in muscle, kidney and heart (not liver) overcome by dietary carnitine therapy
Secondary: Genetic defect in beta oxidation resulting in increased level of acylcarnitines.
What happens to metabolism in primary carnitine metabolism disorders?
Long chain FA oxidation is compromised and this effect is overcome by dietary carnitine therapy
What happens in secondary carnitine metabolism disorders?
Carnitine is excreted in urine
in type I muscle weakness and myoglobinuria
In type II (in infants) it is precipitated by fasting causing hypoketotic, cardiac malfunction and death
How is secondary carnitine metabolic disorders treated?
By avoiding starvation and diet low in long chain fatty acids
What are ketone bodies?
Lipid based energy source that is water soluble and produced primarily by the liver. They are used by CNS in starvation as well as skeletal and cardiac muscle.
What do neonates use ketone bodies for?
Precursors for lipid synthesis
What kind of molecules are ketone bodies?
Ketone bodies are acidic (ketone bodies is a bad name)
What are the products of ketone synthesis?
2 Acetyl-CoA molecules are converted into beta-hydroxybutyrate and acetone (dead end product responsible for fruity breath)
What are the roles of fatty acids in the body?
Fuel storage
Signalling
Components of membrane lipids
What happens in the liver when excess alcohol is consumed?
Alcohol conversion to FA in alcoholic liver disease contributes to liver failure
Which fatty acids does the body need to get from external sources?
Highly unsaturated fatty acids with double bonds near the methyl end (omega 3s)
What is the main pathway for FA synthesis?
Acetyl CoA -> Palmitic acid (16:0, saturated)
Other fatty acids can be made from palmitic acid
Where does fatty acid synthesis occur?
Cytosol of liver and mammary glands
What are the 3 stages of fatty acid synthesis?
Acetyl CoA transport
Acetyl CoA activation
Consecutive 2C addition
What does fatty acid synthesis use as a starting point?
Acetyl CoA
Why is acetyl CoA in the mitochondria?
We make it from pyruvate dehydrogenase
We transport it into the mitochondria
How is acetyl CoA transported into the cytosol?
It combines with oxaloacetate to form citrate which can be moved out of the mitochondria
What influences where citrate ends up?
Energy needs.
When cells need energy citrate continues in the TCA cycle.
When cell has enough energy citrate is relocated to cytoplasm by transport protein acetyl CoA is diverted from TCA cycle so cell can store energy
What is the result of shuttling citrate to the cytosol?
Citrate inhibits phosphofructokinase which in turn stops glycolysis while fatty acid synthesis is taking place.
How are fatty acids synthesized from acetyl CoA in the cytosol?
Acetyl CoA in cytosol
Acetyl CoA is converted to malonyl CoA (activation stage)
Consecutive addition of 2C units by FA synthase
How is malonyl CoA made from acetyl CoA?
Acetyl CoA + HCO3- —-> Malonyl CoA (activated form and is the main regulated step of FA biosynthesis)
What enzyme is used for malonyl CoA production?
Acetyl CoA carboxylase which contains biotin
How many functional regions does acetyl CoA carboxylase have? What else is needed for its function?
3 functional regions, 2 enzymatic subunits, uses ATP
What does fatty acid synthase do?
Multi enzyme polypeptide contains all necessary catalytic activities in a linear array. Works as a dimer. Growing FA chain is continually bound to enzyme keeping intermediates within the complex and reducing side reactions.
Occurs in the cytosol. Requires NADPH, malonyl CoA and Acetyl CoA.
Releases CO2 with every cycle
What cofactor does fatty acid synthase contain?
Acyl carrier protein prosthetic group contains pantothenic acid (Vitamin B5)
How is acetyl CoA carboxylase activated and what can be done if that activation is not possible?
Phosphorylation inactivates carboxylase but then citrate can partly activate Acetyl CoA carboxylase even after phosphorylation
Which hormones trigger phosphorylation and thus inactivation of Acetyl CoA carboxylase?
Glucagon and epinephrine
What does insulin do to Acetyl CoA carboxylase?
Stimulates phosphatase so activates carboxylase
How is fatty acid synthesis regulated?
Regulation of malonyl CoA
Transport into mitochondria
How is beta oxidation inhibited while synthesizing fatty acids?
Malonyl CoA inhibits Acyl-carnitine
What other actions can fatty acids be made for?
Polyunsaturated FAs can be produced from palmitic acid and these polyunsaturated FAs can be processed into a variety of signalling molecules such as leukotrienes and prostaglandins
What fatty acid is commonly used for signalling?
Arachidonate
What happens to FA synthase in cancer?
Fatty acid synthase – overexpressed in many cancers & expression correlates with tumour malignancy.
In tumours, FA not stored for energy, but used to make phospholipids for cell membranes in rapidly growing
cancer cells.
In mice, inhibitors of fatty acid synthase slow tumour
growth & induce cell death.
Mice given enzyme inhibitor also had significant weight
loss.
Where does protein go after ingestion?
Amino acids can be broken down into non-protein nitrogen or stored in tissue.
Amino acids can be glucogenic or ketogenic forming either carbohydrates or ketone bodies.
Amino acids can undergo metabolism through acetyl CoA and then the TCA cycle.
Amino acids can also be deaminated and released from the body in the form of urea
How are amino acid R groups removed?
Via a process called transamination
What happens to amino acids when we have enough of them?
AA degraded and carbons are used in catabolism and anabolism.
Non essential AAs can be synthesized.
AA can only be used for translation. True or False
False, AA can be used for translation and other roles in the cell such as production of neurotransmitters, catecholamines, membrane components, ketone bodies, etc
Do amino acids get stored in the body?
No
What happens to excess AAs?
If not needed for protein synthesis, AA have variety of fates depending on type of AA, tissue it originates from, and body’s needs.
Where is the major site of AA degradation?
Liver
What are the phases of amino acid breakdown?
Phase 1: remove N (alpha amino) from AA creating a keto acid
Phase 2: Alpha keto acid metabolismed so carbon skeleton can enter metabolic pathways: Gluconeogenesis, ketogenesis, or CO2+H2O
What vitamin is essential for aminotransferase activity?
Vitamin B6, pyridoxine
How is a ketoacid created?
Amino transferase moves amino group from the N side of amino acids to another molecule (alphaketoglutarate) creating alpha ketoacid and glutamate
What is the ketoacid for glutamate?
Alpha-ketoglutarate
How is glutamate deaminated?
Oxidatively via glutamate dehydrogenase using NAD+ and H2O to form NADH and NH4+
Why is alpha ketoglutarate commonly used as a substrate for transamination?
Because glutamate dehydrogenase can reverse glutamate production easily to create more alpha ketoglutarate
What does a high concentration of alanine aminotransferase indicate?
Liver damage
What does a high concentration of alanine aminotransferase indicate? What other enzyme indicates the same thing in higher concentrations?
Liver damage, Aspartate aminotransferase
What is the alpha ketoacid of aspartate?
Oxaloacetate
How much of the body’s energy production is caused by AA catabolism?
10 - 15%
How is nitrogen transported in the blood safely?
Either as alanine or glutamine (both produced by transamination)
How does nitrogen get processed using glutamate?
In non-liver or non-kidney tissue glutamine synthetase produces glutamine from glutamate.
Glutamine is then moved to liver and converted into glutamate via glutaminase
How is ammonia removed following amino acid catabolism?
Urea cycle. In the liver and kidneys Ammonia is converted to soluble urea using L-ornithine. Urea is soluble and excreted in urine or processed in the gut by bacteria.
Where does urea N come from?
From NH3 and aspartate
What is ammonium converted into and how?
Carbamoyl phosphate via carbamoyl phosphate synthase
Describe the urea cycle:
Ammonium binds with L-ornithine to form citruline which reacts with aspartate to form arginiosuccinate. Fumarate and arginine are then produced fumarate is a byproduct and arginine combines with water to form urea and more L-ornithine.
What 3 things are needed to form urea?
CO2 ammonia and aspartate (4ATP produce 1 molecule of urea)
Where does the urea cycle take place?
Bulk is in the cytosol but some in the mitochondria
What enzyme produces ornithine and urea?
Arginase
What is the main source of arginine?
Liver and kidneys synthesize it from citruline
Why is cow’s milk a bad idea for neonates?
Cow’s milk is very protein rich and can’t be given full strength to neonates as excess protein exceeds the ability to make urea and thus to excrete N increasing their risk of hyperammonaemia.
Infants have a relatively low urea cycle activity so arginine synthesis is relatively low. How is this fixed?
In periods of rapid growth may need to supplement infants with arginine.
When is a higher level of urea cycle enzyme activity needed?
High protein diet
Starvation (protein being broken down for energy)
How is urea cycle activity increased?
Expression of urea cycle enzymes increases when needed.
Allosteric regulation of carbamoyl phosphate synthase I.
Activated by N-acetylglutamate (precursor of ornithine)
What are the common urea cycle enzyme deficiencies?
OTC deficiency (ornithine trascarbamoylase which produces citruline from carbamoyl phosphate)
Argininosuccinate lyase (Arginino succinic aciduria)
What kind of inheritance is OTC deficiency?
X-linked. Males severely affected and females are variably affected due to random X inactivation
What are the symptoms of OTC deficiency?
Lethargy, poor feeding, abnormal respiration, vomiting, seizures, decreasing conscious level and death (if untreated).
How is OTC deficiency treated?
Restricting protein consumption
What is alkaptonuria?
Decrease in tyrosine degradation due to defective homogentisate 1,2-dioxygenase. Results in dark pigmentation around the body but not usually lethal.
What is maple syrup urine caused by?
Defective isoleucine, valine, and leucine degradation.
It is a disorder of oxidative decarboxylation of alpha-ketoacids derived from branch-chain AAs caused by missing or defective branched-chain dehydrogenase/
Urine has the odour of maple syrup
What enzyme is typically defective in PKU?
Phenylalanine hydroxylase (classical PKU)
What happens in PKU?
Phenylalanine hydroxylase blockage causes decrease in tyrosine and increase in phenylalanine which become phenylketones
What enzyme is blocked in alkaptonuria?
Homogentisate 1,2-dioxygenase
What are the symptoms of alkaptonuria?
In children urine darkens.
In adults darkening of the ear and dark spots on sclera / cornia and arthritis.
Why does alkaptonuria cause its symptoms?
Homogentistic acid accumulates and is excreted in urine. This acid turns black when exposed to air
What are the symptoms of maple syrup urine disease?
Lethargy (earliest symptom)
Poor feeding
Vomiting
Dehydration
Lethargy
Hypotonia
Seizures
Hypoglycaemia
Ketoacidosis
Pancreatitis
Coma
Neurological decline
Unrecognised leads to mental and physical retardation, seizures, coma, and death
What are the general functions of nucleotides?
Making DNA, RNA, and proteins.
Metabolic - ATP, UDP-glucose, etc
Cofactors in biochemical reactions (NAD+)
Cell signalling - cAMP
What pathway is ribose made in?
The pentose phosphate pathway
What happens to dietary nucleic acids?
Nucleoproteins are broken down in the stomach into nucleic acid and protein.
Nucleic acids are broken down in the intestine via DNAse and RNAse into nucleotides.
Nucleotidase is broken down into phosphate and nucleosides.
Nucleosidase breaks nucleosides down into bases and pentose.
How are nucleotides synthesized?
De novo using metabolic precursores (Amino acids, ribose 5-P, CO2, and 1 carbon units.
Salvage pathways: Synthesis of nucleotide by recycling of bases or nucleosides released from nucleic acid breakdown
What is the name of activated ribose?
5-phosphoribosyl 1-pyrophosphate
Where are nucleotides synthesized?
Liver, small intestine, and thymus. Within the cytosol of these cells.
Nucleotides can be synthesized de novo from amino acids, ribose-5-phosphate, CO2 and NH3.
Why must cells constantly synthesize nucleotides?
Nucleotide pools low, they may actually limit rates of transcription and translation.
How are deoxyribonts made?
Ribonts are made first and then reduced to deoxyribonts
Where do carbons and nitrogens used in purines come from?
2 Cs from Formate (from N10-formyl-tetradydrofolate)
C=C-N from Glycine
Amides from glutamine
Aspartate N
C from CO2
Where do carbons and nitrogens come from in pyrimidines?
4 Cs from aspartate
CO2 and glutamine give amino group. (CO2 gives carbon glutamine gives N)
Which enzymes are most important for salvage pathways of purine nucleotides?
Hypoxanthine-Guanine phosphoribosyl transferase (HGPRT)
Adenine phosphoribosyl transferase (APRT)
What does Hypoxanthine-guanine phosphoribosyl transferase do?
Hypoxanthine (an unusual and uncommon purine) can form inosine monophosphate which can make 1 of the 4 nucleotides (hypoxanthine inosine guanine adenine)
What does purine catabolism give?
Uric acid
What results from high amounts of uric acid?
Gout which is a disease of the joints, usually in males, caused by elevated uric acid concentration in the blood and tissues
How is gout treated?
Reducing dietary fat intake to reduce amount of purines in the diet.
What is Lesch-Nyhan syndrome?
An X-linked recessive disease in which people lack HGPRT
What are the clinical symptoms of Lesch-Nyhan syndrome?
Impaired kidney function
Acute gouty arthritis
Self-mutilating behaviour such as lip and finger biting and head banging
Involuntary muscle movements
Neurological impairments
What happens in Lesch-Nyhan syndrome? (pathophysiology)
HGPRT function decreases resulting in build up of activated ribose and low levels of viable purines. Also a high level of purine precursors which get degraded into uric acid causing the symptoms
