Test 4 Flashcards
Finish these sentences about the importance of amino acid metabolism:
- Amino acids are ___ __ of proteins
- Many cellular proteins are constantly ___ and ____ in response to ___ ___ demands of organisms
- Amino acids over those needed for ___ can neither be
___ nor ___, in contrast with fatty acids and glucose - ___ amino acids are used as ___ fuel
- Most of the amino groups harvested from ___ amino acids are converted into ___ through the ___ cycleFin
- Amino acids are building block of proteins
- Many cellular proteins are constantly degraded and resynthesized in response to changing metabolic demands of organisms
- Amino acids over those needed for biosynthesis can neither be stored nor excreted, in contrast with fatty acids and glucose
- Surplus amino acids are used as metabolic fuel
- Most of the amino groups harvested from surplus amino acids are converted into urea through the urea cycle
Dogs and cats have different amino acid requirements, how?
- Dogs inadequately synthesize citrulline
- Most dog breeds convert cysteine into taurine efficiently in the liver.
— Some breeds are more prone to taurine deficiency due to lower hepatic activities of cysteine dioxygenase - De Novo synthesis of arginine and taurine is very limited in cats
- Cats have greater endogenous nitrogen losses and higher requirements for many amino acids than dogs. (Arginine, taurine, cysteine, tyrosine)
Digestion absorption of amino acids
Protein digestion starts in the stomach with pepsin, active at pH 2.
Further the digestion continues in the small intestine at pH 7,4 and is a primary result of the activity of enzymes secreted by the pancreas.
Further aminopeptidase (intestinal epithelium) continues digestion.
Amino acids and di- and tripeptides are absorbed into the intestinal cells by transporters.
Free amino acids get released into blood by transporters for use by other tissues.
The first step of AA degradation is..
The removal of amino group.
- it is first removed and transferred to a-ketoglutarate to form glutamate which is then oxidatively deaminated to release the ammonia
- remaining carbon skeleton is metabolized into:
–> Glucose
–> One of several citric acid cycle intermediates
–> Acetyl CoA - Major site of amino acid degradation in mammals is the liver, although muscles degrade the branched-chain amino acids
What transfers the amino group from a amino acid to keto acid. And which ones in which process.
Aminotransferases transfer the amino groups.
AST (Aspartate aminotransferase) catalyzes the transfer of the amino group aspartate to a-ketoglutarate
– Aspartate + a-ketoglutarate <=> oxaloacetate + glutamate
Alanine aminotransferase catalyzes the transfer of the amino group of alanine to a-ketoglutarate
– Alanine + a-ketoglutarate <=> pyruvate + glutamate
Serine —->
Threonine —->
they are?
Serine —-> Pyruvate + NH4+
Threonine —-> a-ketobutyrate + NH4+
They are both directly deaminated
Oxidative deamination of glutamate occurs….
In the liver mitochondria
- You need a liver -> mitochondria specific enzyme (Glutamate dehydrogenase) for this process
- This compartmentalization sequesters free ammonium ions which are toxic
Glucose-alanine cycle…
Helps to transport amino acid groups from muscle to liver
How does the Glucose-alanine cycle help transport amino acid groups from muscle to liver?
The first step is to remove the nitrogen from the amino acids
Then glutamate can be used to transfer amino group to pyruvate to form alanine
Alanine will then be transported through the blood to the liver
What amino acids do muscles use?
Branched amino acids
– Leucine
– Isoleucine
– Valine
What is Glutamine and what is it essential for?
It is a nonessential amino acid in the body, that is mostly conditionally essential in states of stress
What happens to glutamine in septic and malnourished patients?
It gets depleted in muscles. It is hypothesized that in these patients the availability of glutamine lymphocytes and the gut is reduced, resulting in increased risk of sepsis.
What does amino acid catabolism result in?
It results in waste ammonia that all animals have to excrete.
What does ammonium get converted to in most terrestrial vertebrates?
It gets converted into urea.
Ammoniotelic, Ureotelic and Uricotelic animals
Ammoniotelic animals - Excrete ammonia without converting it
Ureotelic animals - Convert nitrogen into a less toxic substance because they cant easily remove it, such as urea. Via the urea cycle that mainly occurs in the liver. Urea will then be released into the bloodstream where it travels to the kidneys and gets excreted in urine.
Uricotelic animals - Ammonia gets converted to uric acid or urate salt, which is excreted in solid form
The urea cycle begins with..
The formation of carbamoyl phosphate
What does Carbamoyl phosphate react with to form citrulline?
It reacts with ornithine. The reaction is catalyzed by ornithine transcarbamoylase.
Where does citruline condense with aspartate?
In the hepatocyte cytoplasm.
The synthesis of argininosuccinate is catalyzed by?
catalyzed by argininosuccinate synthetase
Argininosuccinate is cleaved into…?
Arginine and fumarate. It does it by using argininosuccinase.
Arginase hydrolyzes…
Arginine to generate urea. The equivalent of four ATP molecules are consumed in this reaction to synthesize one molecule of urea.
What are the urea cycle, gluconeogenesis and transamination linked through?
They are linked through fumarate and aspartate
Inherited defects in the urea cycle can lead to..
Hyperammonemia and brain damage
What can help partly bypass the effects of argininosuccinate deficiency?
Providing surplus of arginine in the diet and restricting total protein intake
What can treat Carbamoyl phosphate or ornithine transcarbamoylase deficiency?
Providing large amounts of benzoate and phenylacetate
What molecules are the carbon skeletons of the 20 fundamental amino acids funneled into?
7 molecules:
- Pyruvate
- Acetyl CoA
- Acetoacetyl CoA
- a-ketoglutarate
- Succinyl CoA
- Fumarate
- Oxaloacetate
What are amino acids that are degraded to acetyl CoA or acetoacetyl CoA termed?
Ketogenic amino acids, because they can give rise to ketone bodies or fatty acids
What are amino acids that get degraded to pyruvate, a-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate termed as?
Glucogenic amino acids
Fates of the carbon skeletons of amino acids
Leucine and lysine are solely ketogenic
Isoleucine, phenylalanine, tryptophan and tyrosine are both ketogenic and glucogenic
How many carbon amino acids is pyruvate an entry point for?
3 carbon amino acids
- Alanine
- Serine
- Cysteine
How many carbon amino acids is oxaloacetate an entry point for?
4 carbon amino acids
- Aspartate
- Asparagine
How many carbon amino acids is alpha-ketoglutarate an entry point for?
5 carbon amino acids
- These are first converted into glutamate
- Glutamine
- Proline
- Arginine
- Histidine
What type of amino acids is succinyl CoA an entry point for?
Non-polar amino acids
- Methionine
- Valine
- Isoleucine
Branched chain amino acids get degraded to…
Acetyl CoA, acetoacetate and propionyl CoA
What is required for degradation of aromatic amino acids?
Oxygenases,
This degradation yields common intermediates like acetoacetate, fumarate and pyruvate
What is the tryptophan idol ring degraded to?
Acetoacetate
Inborn errors of metabolism can disrupt..?
amino acid degradation
Normal intermediate in the degradation of phenylalanine and tyrosine..
Homogentisate, accumulates in alcaptonuria and is excreted in the urine.
Maple syrup urine disease is when?
The oxidative decarboxylation of a-ketoacids derived from valine, isoleucine and leucine is blocked because the branched-chain dehydrogenase is missing or defective.
What is phenylketonuria caused by?
It is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor
Essential amino acids
- Histidine
- Isoleucine
- Leucine
- Lysine
- Methionine
- Phenylalanine
- Threonine
- Tryptophan
- Valine
How are nonessential amino acids synthesized and what are the key elements?
They are synthesized from a-keto acids by transfer a-amino acid from another amino acid by aminotransferases
Key elements are Glutamate and Glutamine
Glutamate and glutamine synthesis
Glutamate is synthesized when ammonia gets incorporated into a-keto-glutarate by glutamate dehydrogenase
Glutamine is synthesized by using ammonia and glutamate as substrates for glutamine synthetase
Synthesis of aspartate and aspargine
Aspartate gets synthesized by combining glutamate and oxaloacetate. The enzyme is Aspartate aminotransferase.
Asparagine gets synthesized by aspartate and glutamine. Using the enzyme Asparagine synthetase
Alanine synthesis
Happens by putting together glutamate and pyruvate with the enzyme alanine transaminase
Tyrosine synthesis
Happens with phenylalanine and the enzyme phenylalanine hydroxylase
Proline synthesis
It starts with glutamate which gets converted to glutamate semialdehyde.
Glutamate semialdehyde gets combined with glutamic acid.
Serine synthesis
Starts with 3-phosphoglycerate, which is the intermediate of glycolysis and uses phosphorylated intermediates in all other steps
Enzymes used are:
- 3-phosphoglycerate dehydrogenase
- aminotransferase
- phosphoserine phosphatase
Cysteine synthesis
The synthesis starts with the transfer of sulfur atoms derived from homocysteine to the hydroxyl group of serine.
This step gives us cystathionine.
Further, by action of cystathionine lyase, cysteine is formed.
Enzymes used:
- Cystathionine – synthase
- Cystathionine – lyase
What do cats lack and what can they do to fix it?
They lack the enzymatic machinery to produce taurine.
They can substitute it in their diets.
What can taurine deficiency in cats lead to?
- Retinal degeneration and eventual blindness
- hair loss
- tooth decay
dilated cardiomyopathy - reproductive failure in female cats
The different histidine derivatives
- Histamine
- Carnosine
- Anserine
Tyrosine derivatives
Catecholamines:
- Dopamine
- Noradrenaline
- Adrenaline
And
- melanins
- Thyroid hormones
Tryptophan derivatives
- Serotonin
- Melatonin
Arginine derivatives
- Spermine
- Spermidine
Glutamate derivatives
- y - aminobutyric acid (GABA)
Base + Sugar =
Base + Sugar + Phosphate =
For Diphosphates
For triphosphates
Base + Sugar = Nucleoside
Base + Sugar + Phosphate = Nucleotide
Diphosphate (GDP, ADP) = guanoside diphosphate, adenosine diphosphate
Triphosphate (GTP, ATP) = Guanosine triphosphate, Adenosine triphosphate
5 Nucleotide functions
- Basic structual elements of nucleic acids
- ATP main source of energy in biological systems
3.Components of Coenzymes (NAD+, NADP+, FMN, FAD, coenzyme A)
- Act as a second messenger in intracelluler signal transmission (cAMP)
- Active forms of many compounds are created by combining nucleotides (E.g. UDP glucose is involved in oglio- and polysaccharides, CDP amino alcohols are involved in the synthesis of phospholipids)
Production of nucleotides
Majority by de novo synthesis.
Some by reusing existing nitrogen bases, through the so called salvage synthesis.
key enzyme in nucleotide synthesis
PRPP synthetase
How is PRPP synthetase activated
Inorganic phospate activates the synthetase.
NDP and NTP act as competitive inhibitors.
Availability of ribose-5-phosphate produced by the pentose phosphate cycle stimulates synthetase activity.
Origins of atoms in the purine ring
Glycine
Aspartate
glutamine
N10- formyltetrahydrofolate
CO2
Location of enzymes involved in purine synthesis
Cytosol
1st step involved in the synthesis of IMP
- Formation of
5-phosphoribosylamine from PRPP and glutamine in a reaction catalyzed by glutamine (PRPP amidotransferase) (Key reaction in the synthesis of purinenucleotides)
What do many steps of Imp synthesis consist of?
Activation of a carbon-bound oxygen atom (typically a carbonyl oxygen atom) by phosphorylation, followed by the displacement of the phosphoryl group by ammonia or an amine group acting as a nucleophile
Biosynthesis of AMP and GMP
Regulation of purine synthesis
Glutamine:PRPP amidotransferase is regulated allosterically by
(1) IMP,AMP and GMP acting as a negative aloosteric effectors
(2)PRPP, acting as a positive allosteric effector
Adenylsuccinyl synthetase is inhibited by AMP
IMP dehydrogenase is inhibited by GMP
The GMP synthesis pathway requires ATP and the AMP synthesis requires GTP
Purine salvage pathways
Provide economical means of generating purines
Free purine bases, derived from the turnover of nucleotides or form the diet, can be attached to PRPP to form purine nucleoside monophosphates
Slavaging Purine
Adenine phosphoribosyltransferase catalyzes the formation of adenylate (AMP)
Adenine +PRPP = adenylate + PPi
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) catalyzes the formation of guanylate (GMP) as well as inosinate (IMP)
Guanine + PRPP = inosinate + PPi
De novo synthesis of pyrmidines
Carbamoyl phosphate is produced by cytosolic carbamoyl phosphate synthetase II (CPS II), a different enzyme than mirochondrial carbamoyl phosphate synthetase I (CPS I) involved in the urea cycle.
Pyrimidine nucleotides sythesis pathway
Carbamoyl phosphate reacts with aspartate to form carbamoylaspartate in a reaction catalyzed by aspartate transcarbamoylase.
Carbamoylasparate then cyclizes to form dihydroorotate, which is then oxidized by NAD+ to form orotate.
Orotic acid is transferred to a PRPP molecule by orotate phosphoribosyltransferase, resulting in orotidine-5’-monophosphate (OMP)
Orotidylate to Uridylate
Orotidylate is decarboxylated to form uridylate (UMP), a major pyrimidine nucleotide which is a precursor to RNA
Reaction catalyzed by orotidylate decarboxylase
Both orotate phosphoribosyltransferase and orotidylate decarboxylase form UMP synthase complex
2 causes of Hereditary deficiency in UMP synthase in dairy cows
- Deficiency of orotate phosphoribosyltransferase and orotidinal decarboxylase.
- Only decarboxylase (Less common)
Orotate aciduria treatment
Administering uridine
Formation of 5’-CTP
Amination of C4 of Uracil of 5’-UTP
Salvage pathways for pyrimidine synthesis.
- Cytosine + PRPP → CMP + PPi
- Uracil + PRPP → UMP + PPi
- Thymine + deoxyribose-1-phosphate→
thymidine + Pi - Thymidine + ATP → TMP + ADP
Acyclovir
Antiviral drug targeting thymidine kinase
Viral thymidine kinase
200x stronger bind to acyclovir than mammalian thymidine kinase
Converts acyclovir to acyclovir monophosphate which phosphorylates to acyclovir triphosphate. This competes with dGTP for DNA polymerase and acts as a chain terminator in viral DNA
Regulation of pyrimidine synthesis
Key rugulatory enzyme - Carbamoyl
phosphate synthetase II.
Inhibited by- CTP
Activated by- PRPP
Types of reactions catalyzed by nucleoside monophosphate kinases
ATP + NMP → ADP + NDP
E.g. ATP + AMP → 2ADP (i.e. ADP + ADP)
Types of reactions catalyzed by nucleoside diphosphate kinases
NTP(D) + NDP(A) → NDP(D) + NTP(A)
(D) = donor (A) = acceptor
Synthesis of deoxynucleotides
Formation starts by reduction of Synthesis of deoxynucleotides.
Then ribonucleotide reductase converts all 4 ribonucleotide diphosphates, drawing its
reducing power from NADPH + H
Ribonucleotide reductase
Atrractive target for cancer therapy
Suicide Inhibitor- gemcitabine which is used in advanced treatment of pancreatic cancer
Allosteric inhibitors- clofarabine and cladribine which treats leukimia (Clofarabine- pediatric acute myeloid leukemia.
Cladribine- chronic lymphoid leukemia.)
Biosynthesis of thymidylate (dTMP)
(Deanimase) dCTP → (dUTPase) dUTP→ (Thymidilate synthase) dUMP→ dTMP
5-Fluorouracil
Suicide inhibitor of Thymidylate synthase and an anticancer drug.
Converted in vivo into fluorodeoxyuridylate which ireversibly inhibits thymidylate synthase
Dihydrofolate reductase
Attractive target for anticancer therapy and catalyzes the regeneration of tetrahydrofolate which is accomplished by
dihydrofolate reductase with the use of NADPH as the reductant.
Aminopterin and methotrexate
(amethopterin, used is treatment of tumors), are potent competitive inhibitors of dihydrofolate reductase
Catabolism of nucleic acids and nucleotides
DNA and RNA are degraded by nucleases.
Nucleotidases release phosphate groups from nucleotides, transforming them into
nucleosides.
Adenosine deaminase (ADA) catalyzes:
Adenosine + H2O → Inosine + NH3 (Reversible)
Purine nucleotide phosphorylases (PNPs) catalyze the following reactions:
Inosine + Pi → hypoxanthine + ribose-1-P (reversible)
Guanosine + Pi → guanine + ribose-1-P (reversible)
Guanine deaminase catalyzes:
Guanine + H2O ,=. Xanthine + NH3
Catabolism of purine nucleotides
Hypoxanthine and guanine oxidised to form xanthine, which is then oxidized to uric
acid.
Urate oxidase (Absent in humans, primates anddalmatians) converts uric acid into
allantoin.
Catablosim of pyrimidine nucleotides
Pyrimidine nucleotides are degraded to nucleosides by nucleotidases:
CMP → cytidine + Pi
dCMP →deoxycytidine + Pi
UMP →uridine + Pi
dTMP → deoxythymidine + Pi
Adenosine deaminase (ADA) deficiency
Severe combined immunodeficiency (SCID), severe recurrent infections often leading to death in early childhood. Loss of T lymphocytes is characteristic.
An increase of 50- 100x in the level of dATP, which is an inhibitor of ribonucleotide reductase, is observed and, as a consequence, there is no dNTP biosynthesis.
Gout
Urate is the final, excreted product of
purine degradation.
High concentration of urate in blood serum (hyperuricemia) causes a painful joint disease - gout where monosodium urate salts crystallize in joints
Where did Phoenicians extract the royal extract from to dye the garments of their royal family
purpura mollustus
Who was the 1st to recognise porphyrin
Hippocrates
What was porphyrin referred to as
blood/liver disease
When was the role of porphyrin pigments established and by who
1871 by Felix Hoppe-Seyer
Who described the clinical syndrome as porphyria
B.J. Stokvis
Who are porphyrins
Groups of heterocyclic compounds composed of 4 pyrrole subunits interconnected by methyne bridges (CH-)
What is a pyrole ring
What does a porphyrin look like
What are the substituents on uroporphyrin 3
acetate (-ch2coo-) and proprionate (-ch2ch2coo-)
Differences between uroporphyrin 1 and 3 and for coporphyrin 1 and 3.Where are each of these molecules also found
For uroporphyrin 1 the p is located on top and the a on the bottom. Vice versa for uroporphyrin 3.For coporphyrins its the same but m replaces a. uroporphyrins were first found in urine but not restricted to that. Coporphyrins were isolated from faeces but also found in urine
What do porphyrins form with metal ions
They form complexes that bind to the nitrogen atom of each 4 rings
What happens to heme c molecules in comparison to heme b molecules
In heme c the vinyl groups of heme b
are replaced by covalent thioether
links to an apoprotein, typically via
cysteinyl residues. Unlike heme b,
heme c thus does not readily
dissociate from its apoprotein
What is vitamin B12 also called
cobalamine
Functions of vitamin B12
Needed in:
* Homocysteine methylation to
methionine (methylcobalamin)
* Isomerization of methylmalonyl
S-CoAto succinyl-S-CoA
(deoxyadenosylcobalamin)
* Absorption requires an intrinsic
factor (glycoprotein produced by
parietal cells), which binds
vitamin. B12 of dietary origin
* Vit. B12 is excreted in the bile,
but mostly reabsorbed from the
gastrointestinal tract.
What are the hemeproteins and what are their functions
Hemoglobin
transport of oxygen in blood
Myoglobin
Storage of oxygen in muscle
Cytochrome c
Involvement in the electron transport chain
Cytochrome P450
hydroxylation of xenobiotics
Catalase
Degradation of hydrogen peroxide
Tryptophan pyrrolase
oxidation of tryptophan
What is heme synthesised by
Succingl CoA and glycine
Where does heme synthesis occur
85% in the erythroid precursor cells and the majority of the remainder in hepatocytes
How is heme synthesised
Firstly to a amino b ketoadipate and then to a aminolevulinate.In the 1st reaction ALA synthase is given off (Coa . Sh).In the 2nd reaction ALA synthase is given off (C02).In the 1st reaction pyridoxal phosphate is used up
What happens when 2 aminolevulinate molecules condense.What is given off by this reaction.
porphobilinogen is formed.ALA dehydratase is given off.
What is ALA dehydratase
A zinc metalloprotein, ALA dehydratase is sensitive to inhibition
by lead, as can occur in lead poisoning
What is porphobilinogen
The 1st precursor pyrrole
What is formed from porphobilinogen and what catalyses that reaction
Head-to-tail condensation of four molecules
of porphobilinogen forms the linear
tetrapyrrole hydroxymethylbilane. The
reaction is catalyzed by cytosolic
hydroxymethylbilane synthase
(uroporphyrinogen I synthase)
In the 2nd cyclisation of hydroxymethylbilane what catalyses the reaction
cytosolic uroporphyrinogen III
synthase
What happens in the 1st cyclisation of hydroxymethylbilane
Hydroxymethylbilane can also cyclize
spontaneously to form uroporphyrinogen
I –whose accumulation may lead to
porphyrias (once oxidized it stains urine and
teeth in red)
What is formed from uroporphryrinnogen 1.Is this pathway reversable. What is formed when you remove a carbon from uroporphyringen.What is formed from coproporphyrinogen
Spontaneous hydroxymethylbilane cyclization creates
Uroporphyrinogen I whose accumulation and exposition to light
creates uroporphyrin I (which stains urine in red)
no
coprophyrinogen is formed.
coporphyrin is formed
What enzyme is used in the conversion of uropophyrinogen to coporphyrinogen
uroporphyrinogen decarboxylase
What kind of reaction is this
cytosolic
reaction
How many moieties of uroporphyrinogen III are formed
four acetate moieties
What is coprophorynogen converted to and wheres it converted
Coproporphyrinogen III enters mitochondria
and is converted to protoporphyrinogen III,
and then to protoporphyrin III
What catalyses the 1st reaction
catalyzed by
coproporphyrinogen oxidase which
decarboxylates and oxidizes the two
propionic acid side chains to form
protoporphyrinogen III
What catalyses the 2nd reaction
protoporphyrinogen oxidase
How is heme formed
Ferrochelatase adds Fe2+ ion to protoporphyrin III
forming Heme
How many isozymes of ALA synthase are there and what are the differences
There are two isozymes of ALA synthase.
ALAS1–expressedthroughout the body
ALAS2–expressed in erythrocyteprecursor cells
ALAS1 isa short-livingenzymewhoseproductionisupregulatedby the lackof
heme. The presenceof hemediminishesitsproduction. ALAS1 level increases
whenthe cytochromeP450 isproducedfor the detoxification
Possibly due to potential lethality, there is noknown defect of ALAS1. Individuals
with low ALAS2 activitydevelop anemia, not porphyria. Porphyriaconsequent to
low activity of ALA dehydratase, termed ALAdehydratase-deficient porphyria, is
extremely rare
How to detect porphyrins
Spectrophotometry
Differences between porphyrins and porphyrinogens. What is the fluorescence absorption and spectra and why
Porphyrinogens are colorless, the various
porphyrins are colored. The conjugated
double bonds in the pyrrole rings and
linking methylene groups of porphyrins
(absent in the porphyrinogens) are
responsible for their characteristic
absorption and fluorescence spectra with
the maximum of 400 nm
What is the purpose of photodynamic therapy. How does it work? What is it also called? What kind of treatment is it?
Photodynamic therapy uses a drug that is
activated by light, called
a photosensitizer or photosensitizing agent, to
kill cancer cells. The light can come from
a laser or other source, such as LEDs.
Photodynamic therapy is also called PDT.
Photodynamic therapy is most often used as a
local treatment, which means it treats a specific
part of the body
What are the FDA approved photodynamic therapies of
cancer(humanmedicine)
*actinic keratosis
*advancedcutaneous T-cell lymphoma
*Barrett esophagus
*basal cell skin cancer
*esophageal(throat) cancer
*non-small cell lung cancer
*squamous cell skin cancer(Stage0)
Other times FDA approved photodynamic therapies of cancer is used
*esophageal cancerwhen it blocks the throat
*non-small cell lung cancer when it blocks the airways
What are the medical characteristics of porphyrins
- they have a low toxicity, high tumor uptake, and stability in the ultraviolet to near infrared
region - they absorb light in the therapeutic window wavelength regionand produce reactive
oxygenspecies(ROS)through the intersystem crossing, allowing them to perform very
well within photodynamictherapy(PDT)and photothermal therapy(PTT)cancer
treatment applications - Their ability to auto-fluoresce within the 400 to 440 nm wavelength region (Soretband)
has also made them reliable for photodynamicdiagnostics (PDD)applications, such as
fluorescence imaging, magnetic resonance imaging (MRI), Raman and photoacoustic
imaging (PAI)
What happens during photodynamic therapy
What do the symptoms of porphyria result from
Symptoms of porphyria result either from a deficiency of intermediates beyond
the enzymatic block, or from the accumulation of metabolites prior to the block.
Main types of porphyrias and their symptoms
How are porphyrias inherited
Most porphyrias are inherited in an autosomal dominant
manner, congenital erythropoietic porphyria is inherited in a recessive mode.
Whats the defective enzyme in congenital erythropoietic porphyria
uroporphyrinogen III synthase,
What does CEP cause at its worst
At its worst, CEP causes appalling photo mutilations from the light-activated porphyrins,
including loss of facial features and fingers, scarring of the cornea and blindness
What is the defective enzyme in Acute intermittent porphyria
hydroxymethylbilane synthase
(uroporphyrinogenI synthase) ,ALA and porphobilinogen accumulate in body tissues and fluids
Most notable symptoms for people with AIP
In AIP the most notable symptoms are neurological attacks, such as trances, seizures and
hallucinations, which often persist over days or even weeks. Luckily, most people with AIP
have a latent form, and never develop any symptoms.
What famous figure suffered from AIP
King George III
Different types of porphyria
Porphyrias may be termed erythropoietic or hepatic based on the organs most affected, typically bone
marrow and the liver
How does drug induced porphyria work
Certain drugs (eg, barbiturates, griseofulvin) induce the production of cytochrome P450. In patients with
porphyria, this can precipitate an attack of porphyria by depleting heme levels. The Compensating
derepression of synthesis of ALAS1 then results in increased levels of potentially harmful heme
precursors.
Possible treatments of porphyrias
In most cases of porphyria, blood or heme transfusions can supply some relief from the symptoms, and
this is still the mainstay of treatment.
Heme infusions help in the treatment of porphyria patients in two ways. First, they overcome the body’s
shortage of heme, relieving anemia. Second, the extra heme suppresses further heme synthesis via a
negative feedback loop.
Avoiding drugs that induce production of cytochrome P450, ingestion of large amounts of carbohydrate,
and administration of hematin to repress ALAS1 synthesis to diminish production of harmful heme
precursors.
CEP can be cured by bone-marrow transplantation, which replaces the faulty stem cells with fully
functional ones. Bone-marrow transplants have been carried out successfully in at least five children with
CEP, usually within the first few years of life.
Drawing blood (phlebotomy) can also help, because this quickly removes porphyrin intermediates from
the circulation. In most cases, some degree of normality can be restored within a few days of an attack.
Patients exhibiting photosensitivity benefit from sunscreens and possibly from administered β
carotene, which appears to lessen production of free radicals, decreasing photosensitivity.
How is hemoglobin from erythrocytes depleted
- globinis degraded to its constituentamino acids,
- iron enters the iron pool(ferritinstore)and can be reused.
- The iron-free porphyrin portion of heme is degraded, mainly in the
reticuloendothelial cells of the liver, spleen, and bone marrow.
What happens in the degradation of heme
What does bilirubin form in the liver
In liver, bilirubin is conjugated to glucuronic acid
to form diglucuronide.
How soluble is bilirubin at pH value? What is bilirubin also transported to the liver by and in
Bilirubin is poorly soluble in aqueous solutions at
physiological pH values.
Therefore, in plasma, bilirubin is transported to
liver by albumin.
What does bilirubin form and how is it formed
Bilirubin forms bilirubin diglucuronide. In normal bile the bilirubin diglucuronide is the
major form of excreted bilirubin.
The glucuronide residues are released in the
terminal ileum and large intestine by bacterial
hydrolases. The released bilirubin is reduced to
the colorless tetrapyrroles called urobilinogens,
which became oxidized to colored products
known as urobilins, which are excreted in the
feces.
What is hyperbilirubinemia and what does it cause
Hyperbilirubinemia, a blood level that exceeds 1 mg of bilirubinper dL(17 μmol/L), may result from the
production of more bilirubin than the normal liver can excrete
Or the failure of a damaged liver to excrete normal amounts of bilirubin
In the absence of hepatic damage, obstruction of the excretory ducts of the liver prevents the excretion of
bilirubin, and will also cause hyperbilirubinemia.
When the blood concentration reaches 2 to 2.5 mg of bilirubin per dL, it diffuses into the tissues, which turn
yellow, a condition termed jaundice or icterus.
What are the different types of hyperbilirubemia and jaundice
retention hyperbilirubinemia-due to overproduction of bilirubin (for example due to the
hemolyticanemias<4mg/dL)
regurgitation hyperbilirubinemia-due to reflux into the bloodstream because of biliary
obstruction.
Because only conjugated bilirubin can appear in the urine, choluric jaundice (choluria is the
presence of bile pigments in the urine) occurs only in regurgitation hyperbilirubinemia and
acholuric jaundice occurs only in the presence of an excess of unconjugated bilirubin(not
present in the urine)
Neonatal jaundice. What is it, how is it formed and what results from it.
Results from accelerated hemolysis and an immature hepatic system for the uptake,
conjugation, and secretionof bilirubin.
Bilirubin glucosyltransferase activity, and also the synthesis of UDP-glucuronate, are reduced
When the plasma concentration of unconjugated bilirubin exceeds that which can be tightly
bound by albumin (20-25 mg/dL), bilirubin can penetrate the blood-brain barrier. If left
untreated, the resulting hyper bilirubinemic toxic encephalopathy
Exposure of jaundiced neonates to blue light (phototherapy) promotes hepatic excretion of
unconjugated bilirubin
Laboratory findings in patients with different jaundice
Summary Part 1
- The heme of hemoproteins such as hemoglobin and thecytochromes is an iron-containing porphyrin consisting
of fourpyrrole rings joined by methynebridges. - A total of eight methyl, vinyl, and propionyl substituents on thefour pyrrole rings of heme are arranged in a
specific sequence. - The metal ion (Fe2+ in hemoglobin; Mg2+ in chlorophyll) islinked to the four nitrogen atoms of the pyrrole rings.
- Biosynthesis of the heme ring involves eight enzyme-catalyzedreactions. Some of these reactions occur in
mitochondria,others in the cytosol. - Synthesis of heme commences with the condensation ofsuccinyl-CoA and glycine to form δ-aminolevulinate(ALA)
- Synthesis of ALAS1 increases in response to a low level of available heme. Certain drugs (eg, phenobarbital)
indirectly trigger enhanced synthesis of ALAS1 by promoting the synthesis of cytochrome P450, which depletes the
heme pool
Summary part 2
- Genetic abnormalities of seven of the eight enzymes of hemebiosynthesis result in inherited porphyrias.
- Erythrocytesand liver are the major sites of expression of the porphyrias.
- Photosensitivity and neurologic problems are commoncomplaints. Intake of certain toxins (eg, lead) can cause
acquired porphyrias. Increased amounts of porphyrins or their precursors can be detected in blood and urine,
facilitating diagnosis - Catabolism of the heme ring, initiated by the mitochondrial enzyme heme oxygenase, produces the linear
tetrapyrrole,biliverdin. Subsequent reduction of biliverdin in the cytosol forms bilirubin. - Bilirubin binds to albumin for transport from peripheral tissues to the liver, where it is taken up by hepatocytes. The
ironof heme is released and reutilized. - The water solubility of bilirubin is increased by the addition of two moles of the highly polar glucuronate, per mole of
bilirubin.
What are the 8 major metabolic pathways?
- Glycolysis
- Fatty acid oxidation
- Degradation of amino acids
- Citric acid cycle
- Oxidative phosphorylation
- Hexose monophosphate shunt
- Gluconeogenesis
- Glycogen metabolism
What mechanism regulates the metabolic pathways?
- the availability of substances
- covalent modification of enzymes
- Allosteric regulation
- Regulation of enzyme synthesis
What does the liver specialize in?
- Serving as the body’s central metabolic clearing house
- Processes and distributes the nutrients to different tissues
- After meals the liver takes up carbohydrates, lipids and most of the amino acids to process them and route them to other tissues
What are the major metabolic functions of the liver?
- Carbohydrate metabolism
- Lipid metabolism
- Protein metabolism
What is adipose tissue? How much is stored in a normal adult man?
It is the energy storage tissue
about 15 kg (135,000 cal) are stored in an adult man
What are the major metabolic functions of the adipose tissue?
- Carbohydrate metabolism
- Lipid metabolism
How much oxygen does skeletal muscle use? What are them major metabolic functions of the skeletal muscle?
It uses 30% of oxygen when its resting and 90% when its exercising
The major metabolic functions are:
1. Carbohydrate metabolism
2. Lipid metabolism
3. Protein metabolism
How much of the body’s weight is the brain? How much oxygen does it use? And what are its most important metabolic functions?
Its about 2% of the body’s weight
It uses around 20% oxygen
Its major functions:
1. Carbohydrate metabolism
2. Lipid metabolism
Energy relationship in major mammalian organs
