Biochemistry II Flashcards
What enzyme deficiency results in methemoglobinemia?
Cytochrome b5 reductase deficiency
- Fe3+ doesn’t carry O2
What molecule helps modulate O2 binding to Hb?
2,3 Bisphosphoglycerate
What reaction does lead poisoning interfere with?
Aminolevulinic Acid –> Porphobilinogen + H20
Enzyme: ALAD
Causes sideroblastic anemia
(Second reaction in heme production)
What is acute intermittent porphyria?
Autosomal dominant, half normal levels of Porphobilinogin Deaminase
Marked increase of urinary ALA and PBG
Clinical Manifestations:
Acute attacks with variable neurologic and visceral symptoms
Severe abdominal pain
Tachycardia, agitation, psychiatric symptoms
What is Porphyria Cutanea Tarda?
Most common porphyria
Decreased Uroporphyrinogen Decarboxylase
Excess uroporphyrin III excreted in urine
Cutaneous and hepatic involvement in the absence of neurological symptoms
Chronic blistering lesions on sun-exposed areas of skin
Symptoms develop in adulthood
What can precipitate an attack of Porphyria Cutanea Tarda?
Chemical exposure
Drugs
Smoking
Alcohol
–> anything that affects p450 enzymes and increases teh need for heme
Which porphyrias are photosensitive?
Any that produce an accumulation of excess pophyrinogens - which release ROS at their light excited state
Congenital erythropoietic porphyria (Uroporphyrinogen II cosynthase)
Porphyria Cutanea Tarda (Urophorphyrinogen Decarboxylase)
Hereditary Coproporphyria (Coproporphyrinogen oxidase)
Variegate Porphyria (Protoporphyrinogen oxidase)
Erythropoietic Protoporphyria (Ferrochelatase)
Which porphyrias are Autosomal Dominant, which are recessive?
Dominant:
- *ALAD porphyria** (ALAD)
- *Acute Intermittent Porphyria** (porphobilinogen deaminase)
- *Porphyria Cutanea Tarda** (Uropophyrinogen Decarboxylase)
- *Hereditary Coprophophyria** (Copropophyrinogen Oxidase)
- *Variegate Porphyria** (Protoporphyrinogen oxidase)
- *Erythropoietic** Protoporphyria (Ferrochelatase)
Recessive:
Congenital Erythropoietic Porphyria (Uroporphyrinogen III Cosynthase)
How is hemoglobin synthesis regulated?
Heme causes a negative feedback response on ALAS (both inhibiting and down regulating it)
What is gout?
Disease of uric acid and sodium urate crystal deposition
Characterized by:
Hyperuricemia
Recurrent attacks of acute inflammatory arthritis
Acccumulation of urate crystals
uric acid Urolithiasis
Nephropathy
What are the 4 phases of gout?
- Asymptomatic hyperuricemia
- Gouty arthritis - acute attacks
- Intercritical periods
- Chronic tophaceous gout (permanent deformaties)
What is Lesch-Nyhan Syndrome?
Inherited deficiency of purine salvage enzyme Hypoxanthineguanine phosphoribosyltransferase (HGPRT)
X-linked recessive disorder
Symptoms:
Hyperuricemia (extremely high production of uric acid due to altered regulation of purine synthesis and degredation)
neurological problems
Profound motor disability
Hypotonia
Failt to hold up head
Crawling difficult
Self-injurous behavior
How is the scaffold of a purine ring formed?
Pentose Phosphate Pathway produces Ribose 5-phosphate
Ribose 5-Phosphate + ATP–> 5-Phosphoribosyl 1-pyrophosphate (PRPP)
Enzyme: PRPP Synthetase
Super activity of what enzyme will cause hyperuricemia?
PRPP Synthetase
–> Increased PRPP leads to increased IMP, leads to increased purines and uric acid
What are the key reactions in purine salvage pathways?
Adenine + PRPP –> AMP + PPi
Enzyme: APRT
Hypoxantine + PRPP –> IMP + PPi
Guanine + PRPP –> GMP + PPi
Enzyme: HGPRT
What is the committed step for purine synthesis? Why?
Formation of PRA:
PRPP + Glutamine –> PRA
Enzyme: PRA Synthase
Why:
AMP, IMP, and GMP are alosteric inhibitors that are able to synergize and effectively shut off PRA synthase activity
What is the significance of PRPP for purines?
It is a precursor for de novo synthesis
It is a reactant for purine salvage
What are causes of hyperuricemia?
- Increased de novo synthesis of purines caused by increased intracellular concentrations of nonpurine precursors (i.e. PRPP)
- Decreased reutilization of purines due to an HGPRT deficient state (which causes increased levels of PRPP, thus accelerating de novo synthesis)
Deficiencies in what enzymes in the purine salvage pathway leads to primary immunodeficiencies?
- Adenosine Deaminase
- Purine Nucleoside Phosphorylase
–> Levels of adenosine and deoxyadenosine build up and interfere with production of immune system
What deficiency(s) cause hereditary orotic aciduria?
Orate Phosphoribosyltransferase (OPRT)
and
OMP Decarboxylase (OMPDC) Deficiencies
Orotate –> OMP
Enzyme: OPRT
OMP –> UMP
Enzyme: OMPDC
What is the target of hydroxyurea? What is it used to treat?
Ribonucleotide Reductase
NDP –> dNDP
Enzyme: ribonucleotide reductase
Used to treat:
CML
Breast Cancer
etc.
Sickle Cell Anemia
What is the target of 5-Fluorouracil (5-FU)?
Thymidylate Synthase
dUMP –> dTMP
Enzyme: Thymidylate Synthase
Cofactor: Methylene FH4 –> Dihydrofolate
What is the target of methotrexate?
Dihydrofolate reductase
Dihydrofolate –> Tetrahydrofolate
Enzyme: dihydrofolate reductase
What amino acids are essential amino acids?
- *P**henylalanine
- *V**aline
- *T**ryptophan
- *T**hreonine
- *I**soleucine
- *M**ethionine
- *H**istidine
- *A**rginine
- *L**eucine
- *L**ysine
PVT TIM HALL
What is phenylketonuria?
Results from a defect anywhere in the system of enzymes required to take Phe –> Tyr
Generally:
Phenylalaninie Hydroxylase
or
Tetrahydrobiopterin Synthesis
Phe accumulates and converted to phenylketones (give urine a musty odor)
Mental retardation occurs
Treated with a Phe restricted diet
What is Maple Syrup Urine Disease (MSUD)?
Autosomal Recessive
Enzyme complex that decarboxylates the transamination product of branched chain amino acids (Branched chain alph-ketoacid dehydrogenase) is defective
Valine, Isoleucine, and leucine accumulate
Mental retardation and poor myelination of nerves occurs
Dietary restrictions are difficult because essential amino acids are required
What are the mechanisms of ammonia neurotoxicity?
- Excess NH3 shifts Glu/Gln balance towards Gln (loss of neurotransmitter)
- Gln enters mitochondria of astrocytes and is hydrolyzes to Glu + NH3
- Intramitochondrial NH3 increases formation of ROS and opening of mitochondrial transition permeability pore
- NH3 also may increase cell permeabiliity to Ca2+ (causing activation of many pores)
How do blood levels of glucose, insulin, and glucagon differ after a high carbohydrate vs high protein meal?
- *Carbohydrate:**
- Glucose levels rise after meal
- Insulin levels increase 12-fold
- Glucagon levels decrease 1.4-fold
- *Protein:**
- Glucose levels slightly increase
- Insulin levels increase 2.5-fold
- Glucagon levels increase 1.67-fold
What is the sole source of nitrogen in human diets?
amino acids
How is nitrogen stored in the body?
It’s not - it must be used or excreted, any build-up will cause ammonia toxicity
Balance:
- *Zero** or healthy adults
- *Positive** for growth
- *Negative** for protein or essential AA malnutrition or as a “stress” response
Why is urea used for nitrogen secretion?
Non toxic
Water soluble
Combines two waste products: CO2 + NH3
Ammonia is easier to make, but is highly toxic; must be converted to urea
What results from a deficiency of carbamoyl phosphate synthetase I (CPS I)?
An inability for nitrogenous waste (ammonia) to be metabolized via the urea cycle
NH4+ + HCO3- –> Carbamoyl Phosphate
Enzyme: CPS I
ATP also needed
Ammonia levels rise leading to:
Brain damage
Coma
Death
Without strict dietary control
What does a deficiency in ornithine transcarbamoylase result in?
An X-linked deficiency, it results in neurologic sequelae similar to CPSI deficiency
Carbamoyl Phosphate + Ornithine –> Citrulline
Enzyme: ornithine transcarbamoylase
What results from argininosuccinate synthetase deficiency?
Elevation of serum citrulline
Without dietary management, will result in:
lethargy
hypotonia
seizures
ataxia
behavioral changes
Citrulline + Aspartate –> Argininosuccinate
Enzyme: Argininosuccinate synthetase
Uses 1ATP
What results from argininosuccinate lyase deficiency?
Argininosuccinate aciduria
Symptoms:
Hyperammonemia
severe effects on CNS
Argininosuccinate –> Fumarate + Arginine
Enzyme: Argininosuccinate lyase
