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Biochemistry 1 > Test 4 > Flashcards

Test 4 Flashcards

1
Q

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
A
  • 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
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2
Q

Dogs and cats have different amino acid requirements, how?

A
  • 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)
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3
Q

Digestion absorption of amino acids

A

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.

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4
Q

The first step of AA degradation is..

A

The removal of amino group.

  1. it is first removed and transferred to a-ketoglutarate to form glutamate which is then oxidatively deaminated to release the ammonia
  2. remaining carbon skeleton is metabolized into:
    –> Glucose
    –> One of several citric acid cycle intermediates
    –> Acetyl CoA
  3. Major site of amino acid degradation in mammals is the liver, although muscles degrade the branched-chain amino acids
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5
Q

What transfers the amino group from a amino acid to keto acid. And which ones in which process.

A

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

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6
Q

Serine —->

Threonine —->

they are?

A

Serine —-> Pyruvate + NH4+

Threonine —-> a-ketobutyrate + NH4+

They are both directly deaminated

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7
Q

Oxidative deamination of glutamate occurs….

A

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
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8
Q

Glucose-alanine cycle…

A

Helps to transport amino acid groups from muscle to liver

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9
Q

How does the Glucose-alanine cycle help transport amino acid groups from muscle to liver?

A

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

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10
Q

What amino acids do muscles use?

A

Branched amino acids
– Leucine
– Isoleucine
– Valine

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11
Q

What is Glutamine and what is it essential for?

A

It is a nonessential amino acid in the body, that is mostly conditionally essential in states of stress

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12
Q

What happens to glutamine in septic and malnourished patients?

A

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.

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13
Q

What does amino acid catabolism result in?

A

It results in waste ammonia that all animals have to excrete.

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14
Q

What does ammonium get converted to in most terrestrial vertebrates?

A

It gets converted into urea.

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15
Q

Ammoniotelic, Ureotelic and Uricotelic animals

A

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

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16
Q

The urea cycle begins with..

A

The formation of carbamoyl phosphate

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17
Q

What does Carbamoyl phosphate react with to form citrulline?

A

It reacts with ornithine. The reaction is catalyzed by ornithine transcarbamoylase.

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18
Q

Where does citruline condense with aspartate?

A

In the hepatocyte cytoplasm.

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19
Q

The synthesis of argininosuccinate is catalyzed by?

A

catalyzed by argininosuccinate synthetase

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20
Q

Argininosuccinate is cleaved into…?

A

Arginine and fumarate. It does it by using argininosuccinase.

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21
Q

Arginase hydrolyzes…

A

Arginine to generate urea. The equivalent of four ATP molecules are consumed in this reaction to synthesize one molecule of urea.

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22
Q

What are the urea cycle, gluconeogenesis and transamination linked through?

A

They are linked through fumarate and aspartate

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23
Q

Inherited defects in the urea cycle can lead to..

A

Hyperammonemia and brain damage

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24
Q

What can help partly bypass the effects of argininosuccinate deficiency?

A

Providing surplus of arginine in the diet and restricting total protein intake

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25
Q

What can treat Carbamoyl phosphate or ornithine transcarbamoylase deficiency?

A

Providing large amounts of benzoate and phenylacetate

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26
Q

What molecules are the carbon skeletons of the 20 fundamental amino acids funneled into?

A

7 molecules:
- Pyruvate
- Acetyl CoA
- Acetoacetyl CoA
- a-ketoglutarate
- Succinyl CoA
- Fumarate
- Oxaloacetate

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27
Q

What are amino acids that are degraded to acetyl CoA or acetoacetyl CoA termed?

A

Ketogenic amino acids, because they can give rise to ketone bodies or fatty acids

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28
Q

What are amino acids that get degraded to pyruvate, a-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate termed as?

A

Glucogenic amino acids

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29
Q

Fates of the carbon skeletons of amino acids

A

Leucine and lysine are solely ketogenic

Isoleucine, phenylalanine, tryptophan and tyrosine are both ketogenic and glucogenic

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30
Q

How many carbon amino acids is pyruvate an entry point for?

A

3 carbon amino acids
- Alanine
- Serine
- Cysteine

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31
Q

How many carbon amino acids is oxaloacetate an entry point for?

A

4 carbon amino acids
- Aspartate
- Asparagine

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32
Q

How many carbon amino acids is alpha-ketoglutarate an entry point for?

A

5 carbon amino acids
- These are first converted into glutamate

  • Glutamine
  • Proline
  • Arginine
  • Histidine
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33
Q

What type of amino acids is succinyl CoA an entry point for?

A

Non-polar amino acids
- Methionine
- Valine
- Isoleucine

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34
Q

Branched chain amino acids get degraded to…

A

Acetyl CoA, acetoacetate and propionyl CoA

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35
Q

What is required for degradation of aromatic amino acids?

A

Oxygenases,
This degradation yields common intermediates like acetoacetate, fumarate and pyruvate

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36
Q

What is the tryptophan idol ring degraded to?

A

Acetoacetate

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37
Q

Inborn errors of metabolism can disrupt..?

A

amino acid degradation

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38
Q

Normal intermediate in the degradation of phenylalanine and tyrosine..

A

Homogentisate, accumulates in alcaptonuria and is excreted in the urine.

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39
Q

Maple syrup urine disease is when?

A

The oxidative decarboxylation of a-ketoacids derived from valine, isoleucine and leucine is blocked because the branched-chain dehydrogenase is missing or defective.

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40
Q

What is phenylketonuria caused by?

A

It is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor

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41
Q

Essential amino acids

A
  • Histidine
  • Isoleucine
  • Leucine
  • Lysine
  • Methionine
  • Phenylalanine
  • Threonine
  • Tryptophan
  • Valine
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42
Q

How are nonessential amino acids synthesized and what are the key elements?

A

They are synthesized from a-keto acids by transfer a-amino acid from another amino acid by aminotransferases

Key elements are Glutamate and Glutamine

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43
Q

Glutamate and glutamine synthesis

A

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

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44
Q

Synthesis of aspartate and aspargine

A

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

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45
Q
A
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46
Q

Alanine synthesis

A

Happens by putting together glutamate and pyruvate with the enzyme alanine transaminase

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47
Q

Tyrosine synthesis

A

Happens with phenylalanine and the enzyme phenylalanine hydroxylase

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48
Q

Proline synthesis

A

It starts with glutamate which gets converted to glutamate semialdehyde.

Glutamate semialdehyde gets combined with glutamic acid.

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49
Q

Serine synthesis

A

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
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50
Q

Cysteine synthesis

A

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

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51
Q

What do cats lack and what can they do to fix it?

A

They lack the enzymatic machinery to produce taurine.

They can substitute it in their diets.

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52
Q

What can taurine deficiency in cats lead to?

A
  • Retinal degeneration and eventual blindness
  • hair loss
  • tooth decay
    dilated cardiomyopathy
  • reproductive failure in female cats
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53
Q

The different histidine derivatives

A
  • Histamine
  • Carnosine
  • Anserine
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54
Q

Tyrosine derivatives

A

Catecholamines:
- Dopamine
- Noradrenaline
- Adrenaline

And
- melanins
- Thyroid hormones

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55
Q

Tryptophan derivatives

A
  • Serotonin
  • Melatonin
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56
Q

Arginine derivatives

A
  • Spermine
  • Spermidine
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57
Q

Glutamate derivatives

A
  • y - aminobutyric acid (GABA)
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58
Q

Base + Sugar =

Base + Sugar + Phosphate =

For Diphosphates

For triphosphates

A

Base + Sugar = Nucleoside

Base + Sugar + Phosphate = Nucleotide

Diphosphate (GDP, ADP) = guanoside diphosphate, adenosine diphosphate

Triphosphate (GTP, ATP) = Guanosine triphosphate, Adenosine triphosphate

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59
Q

5 Nucleotide functions

A
  1. Basic structual elements of nucleic acids
  2. ATP main source of energy in biological systems

3.Components of Coenzymes (NAD+, NADP+, FMN, FAD, coenzyme A)

  1. Act as a second messenger in intracelluler signal transmission (cAMP)
  2. 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)
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60
Q

Production of nucleotides

A

Majority by de novo synthesis.

Some by reusing existing nitrogen bases, through the so called salvage synthesis.

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61
Q

key enzyme in nucleotide synthesis

A

PRPP synthetase

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62
Q

How is PRPP synthetase activated

A

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.

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63
Q

Origins of atoms in the purine ring

A

Glycine
Aspartate
glutamine
N10- formyltetrahydrofolate
CO2

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64
Q

Location of enzymes involved in purine synthesis

A

Cytosol

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65
Q

1st step involved in the synthesis of IMP

A
  1. Formation of
    5-phosphoribosylamine from PRPP and glutamine in a reaction catalyzed by glutamine (PRPP amidotransferase) (Key reaction in the synthesis of purinenucleotides)
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66
Q

What do many steps of Imp synthesis consist of?

A

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

67
Q

Biosynthesis of AMP and GMP

A
68
Q

Regulation of purine synthesis

A

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

69
Q

Purine salvage pathways

A

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

70
Q

Slavaging Purine

A

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

71
Q

De novo synthesis of pyrmidines

A

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.

72
Q

Pyrimidine nucleotides sythesis pathway

A

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)

73
Q

Orotidylate to Uridylate

A

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

74
Q

2 causes of Hereditary deficiency in UMP synthase in dairy cows

A
  1. Deficiency of orotate phosphoribosyltransferase and orotidinal decarboxylase.
  2. Only decarboxylase (Less common)
75
Q

Orotate aciduria treatment

A

Administering uridine

76
Q

Formation of 5’-CTP

A

Amination of C4 of Uracil of 5’-UTP

77
Q

Salvage pathways for pyrimidine synthesis.

A
  1. Cytosine + PRPP → CMP + PPi
  2. Uracil + PRPP → UMP + PPi
  3. Thymine + deoxyribose-1-phosphate→
    thymidine + Pi
  4. Thymidine + ATP → TMP + ADP
78
Q

Acyclovir

A

Antiviral drug targeting thymidine kinase

79
Q

Viral thymidine kinase

A

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

80
Q

Regulation of pyrimidine synthesis

A

Key rugulatory enzyme - Carbamoyl
phosphate synthetase II.

Inhibited by- CTP
Activated by- PRPP

81
Q

Types of reactions catalyzed by nucleoside monophosphate kinases

A

ATP + NMP → ADP + NDP
E.g. ATP + AMP → 2ADP (i.e. ADP + ADP)

82
Q

Types of reactions catalyzed by nucleoside diphosphate kinases

A

NTP(D) + NDP(A) → NDP(D) + NTP(A)
(D) = donor (A) = acceptor

83
Q

Synthesis of deoxynucleotides

A

Formation starts by reduction of Synthesis of deoxynucleotides.

Then ribonucleotide reductase converts all 4 ribonucleotide diphosphates, drawing its
reducing power from NADPH + H

84
Q

Ribonucleotide reductase

A

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.)

85
Q

Biosynthesis of thymidylate (dTMP)

A

(Deanimase) dCTP → (dUTPase) dUTP→ (Thymidilate synthase) dUMP→ dTMP

86
Q

5-Fluorouracil

A

Suicide inhibitor of Thymidylate synthase and an anticancer drug.

Converted in vivo into fluorodeoxyuridylate which ireversibly inhibits thymidylate synthase

87
Q

Dihydrofolate reductase

A

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

88
Q

Catabolism of nucleic acids and nucleotides

A

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

89
Q

Catabolism of purine nucleotides

A

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.

90
Q

Catablosim of pyrimidine nucleotides

A

Pyrimidine nucleotides are degraded to nucleosides by nucleotidases:
CMP → cytidine + Pi
dCMP →deoxycytidine + Pi
UMP →uridine + Pi
dTMP → deoxythymidine + Pi

91
Q

Adenosine deaminase (ADA) deficiency

A

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.

92
Q

Gout

A

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

93
Q

Where did Phoenicians extract the royal extract from to dye the garments of their royal family

A

purpura mollustus

94
Q

Who was the 1st to recognise porphyrin

A

Hippocrates

95
Q

What was porphyrin referred to as

A

blood/liver disease

96
Q

When was the role of porphyrin pigments established and by who

A

1871 by Felix Hoppe-Seyer

97
Q

Who described the clinical syndrome as porphyria

A

B.J. Stokvis

98
Q

Who are porphyrins

A

Groups of heterocyclic compounds composed of 4 pyrrole subunits interconnected by methyne bridges (CH-)

99
Q

What is a pyrole ring

A
100
Q

What does a porphyrin look like

A
101
Q

What are the substituents on uroporphyrin 3

A

acetate (-ch2coo-) and proprionate (-ch2ch2coo-)

102
Q

Differences between uroporphyrin 1 and 3 and for coporphyrin 1 and 3.Where are each of these molecules also found

A

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

103
Q

What do porphyrins form with metal ions

A

They form complexes that bind to the nitrogen atom of each 4 rings

104
Q

What happens to heme c molecules in comparison to heme b molecules

A

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

105
Q

What is vitamin B12 also called

A

cobalamine

106
Q

Functions of vitamin B12

A

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.

107
Q

What are the hemeproteins and what are their functions

A

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

108
Q

What is heme synthesised by

A

Succingl CoA and glycine

109
Q

Where does heme synthesis occur

A

85% in the erythroid precursor cells and the majority of the remainder in hepatocytes

110
Q

How is heme synthesised

A

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

111
Q

What happens when 2 aminolevulinate molecules condense.What is given off by this reaction.

A

porphobilinogen is formed.ALA dehydratase is given off.

112
Q

What is ALA dehydratase

A

A zinc metalloprotein, ALA dehydratase is sensitive to inhibition
by lead, as can occur in lead poisoning

113
Q

What is porphobilinogen

A

The 1st precursor pyrrole

114
Q

What is formed from porphobilinogen and what catalyses that reaction

A

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)

115
Q

In the 2nd cyclisation of hydroxymethylbilane what catalyses the reaction

A

cytosolic uroporphyrinogen III
synthase

116
Q

What happens in the 1st cyclisation of hydroxymethylbilane

A

Hydroxymethylbilane can also cyclize
spontaneously to form uroporphyrinogen
I –whose accumulation may lead to
porphyrias (once oxidized it stains urine and
teeth in red)

117
Q

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

A

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

118
Q

What enzyme is used in the conversion of uropophyrinogen to coporphyrinogen

A

uroporphyrinogen decarboxylase

119
Q

What kind of reaction is this

A

cytosolic
reaction

120
Q

How many moieties of uroporphyrinogen III are formed

A

four acetate moieties

121
Q

What is coprophorynogen converted to and wheres it converted

A

Coproporphyrinogen III enters mitochondria
and is converted to protoporphyrinogen III,
and then to protoporphyrin III

122
Q

What catalyses the 1st reaction

A

catalyzed by
coproporphyrinogen oxidase which
decarboxylates and oxidizes the two
propionic acid side chains to form
protoporphyrinogen III

123
Q

What catalyses the 2nd reaction

A

protoporphyrinogen oxidase

124
Q

How is heme formed

A

Ferrochelatase adds Fe2+ ion to protoporphyrin III
forming Heme

125
Q

How many isozymes of ALA synthase are there and what are the differences

A

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

126
Q

How to detect porphyrins

A

Spectrophotometry

127
Q

Differences between porphyrins and porphyrinogens. What is the fluorescence absorption and spectra and why

A

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

128
Q

What is the purpose of photodynamic therapy. How does it work? What is it also called? What kind of treatment is it?

A

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

129
Q

What are the FDA approved photodynamic therapies of
cancer(humanmedicine)

A

*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)

130
Q

Other times FDA approved photodynamic therapies of cancer is used

A

*esophageal cancerwhen it blocks the throat
*non-small cell lung cancer when it blocks the airways

131
Q

What are the medical characteristics of porphyrins

A
  • 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)
132
Q

What happens during photodynamic therapy

A
133
Q

What do the symptoms of porphyria result from

A

Symptoms of porphyria result either from a deficiency of intermediates beyond
the enzymatic block, or from the accumulation of metabolites prior to the block.

134
Q

Main types of porphyrias and their symptoms

A
135
Q

How are porphyrias inherited

A

Most porphyrias are inherited in an autosomal dominant
manner, congenital erythropoietic porphyria is inherited in a recessive mode.

136
Q

Whats the defective enzyme in congenital erythropoietic porphyria

A

uroporphyrinogen III synthase,

137
Q

What does CEP cause at its worst

A

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

138
Q

What is the defective enzyme in Acute intermittent porphyria

A

hydroxymethylbilane synthase
(uroporphyrinogenI synthase) ,ALA and porphobilinogen accumulate in body tissues and fluids

139
Q

Most notable symptoms for people with AIP

A

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.

140
Q

What famous figure suffered from AIP

A

King George III

141
Q

Different types of porphyria

A

Porphyrias may be termed erythropoietic or hepatic based on the organs most affected, typically bone
marrow and the liver

142
Q

How does drug induced porphyria work

A

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.

143
Q

Possible treatments of porphyrias

A

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.

144
Q

How is hemoglobin from erythrocytes depleted

A
  • 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.
145
Q

What happens in the degradation of heme

A
146
Q

What does bilirubin form in the liver

A

In liver, bilirubin is conjugated to glucuronic acid
to form diglucuronide.

147
Q

How soluble is bilirubin at pH value? What is bilirubin also transported to the liver by and in

A

Bilirubin is poorly soluble in aqueous solutions at
physiological pH values.
Therefore, in plasma, bilirubin is transported to
liver by albumin.

148
Q

What does bilirubin form and how is it formed

A

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.

149
Q

What is hyperbilirubinemia and what does it cause

A

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.

150
Q

What are the different types of hyperbilirubemia and jaundice

A

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)

151
Q

Neonatal jaundice. What is it, how is it formed and what results from it.

A

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

152
Q

Laboratory findings in patients with different jaundice

A
153
Q

Summary Part 1

A
  • 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
154
Q

Summary part 2

A
  • 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.
155
Q

What are the 8 major metabolic pathways?

A
  1. Glycolysis
  2. Fatty acid oxidation
  3. Degradation of amino acids
  4. Citric acid cycle
  5. Oxidative phosphorylation
  6. Hexose monophosphate shunt
  7. Gluconeogenesis
  8. Glycogen metabolism
156
Q

What mechanism regulates the metabolic pathways?

A
  1. the availability of substances
  2. covalent modification of enzymes
  3. Allosteric regulation
  4. Regulation of enzyme synthesis
157
Q

What does the liver specialize in?

A
  • 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
158
Q

What are the major metabolic functions of the liver?

A
  1. Carbohydrate metabolism
  2. Lipid metabolism
  3. Protein metabolism
159
Q

What is adipose tissue? How much is stored in a normal adult man?

A

It is the energy storage tissue

about 15 kg (135,000 cal) are stored in an adult man

160
Q

What are the major metabolic functions of the adipose tissue?

A
  1. Carbohydrate metabolism
  2. Lipid metabolism
161
Q

How much oxygen does skeletal muscle use? What are them major metabolic functions of the skeletal muscle?

A

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

162
Q

How much of the body’s weight is the brain? How much oxygen does it use? And what are its most important metabolic functions?

A

Its about 2% of the body’s weight

It uses around 20% oxygen

Its major functions:
1. Carbohydrate metabolism
2. Lipid metabolism

162
Q

Energy relationship in major mammalian organs

A

Biochemistry 1 (19 decks)

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