Biochemistry II Flashcards by Karin Golob

What enzyme deficiency results in methemoglobinemia?

Cytochrome b5 reductase deficiency

Fe³⁺ doesn’t carry O₂

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What molecule helps modulate O₂ binding to Hb?

2,3 Bisphosphoglycerate

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What reaction does lead poisoning interfere with?

Aminolevulinic Acid –> Porphobilinogen + H₂0
Enzyme: ALAD

Causes sideroblastic anemia

(Second reaction in heme production)

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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

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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

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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

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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)

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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)

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How is hemoglobin synthesis regulated?

Heme causes a negative feedback response on ALAS (both inhibiting and down regulating it)

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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

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What are the 4 phases of gout?

Asymptomatic hyperuricemia
Gouty arthritis - acute attacks
Intercritical periods
Chronic tophaceous gout (permanent deformaties)

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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

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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

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Super activity of what enzyme will cause hyperuricemia?

PRPP Synthetase

–> Increased PRPP leads to increased IMP, leads to increased purines and uric acid

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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

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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