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Flashcards in Test 1 (Dr. Seidler Nitrogen Lecture) Deck (14):

Hartnup Disease

- The transport of Amino Acids into and out of the cells is mediated by protein transporters.

- Autosomal Recessive diseases such as Hartnup disease and Cystinuria are associated with defects in the transporters for particular Amino Acids, causing them to be concentrated in Urine.

- For instance, Hartunup Disease is caused by a defect in a transporter for NONPOLAR or NEUTRAL Amino Acids (TRYPTOPHAN), which is primarily found in the kidneys and intestine.

- It manifests in Infancy as FAILURE TO THRIVE, Nystagmus (Abnormally rapid and repetitive eye movement), Intermittent Ataxia (Lack of muscle coordination), tremor, and photosensitivity



- Cystinuria is caused by a defect in the transporter system responsible for the uptake of the DIMERIC Amino Acid CYSTINE and the DIBASIC Amino Acid ARG, LYS, and ORNITHINE.

- (Cytine is formed when two CYS are OXIDIZED and linked by a DISULFIDE BOND)

- This results in the formation of CYSTINE CRYSTALS or Stones in the Kidneys (Renal Calculi), which can be identified via a Positive Nitroprusside test.

- Patients with this condition represent with RENAL COLIC (Abdominal Pain that comes in waves and is linked to Kidney Stones)


Maple Syrup Urine Disease

- Maple Syrup Urine Disease is a RARE AUTOSOMAL Disease resulting form a deficiency of BRANCHED- CHAIN ALPHA KETO ACID DEHYDROGENASE activity

- The hallmark of the disease is the presence of Branched-Chain Amino Acids and their Alpha-Keto Derivatives in the URINE of patients, giving the characteristic odor of burnt Maple Sugar.

- These compounds also accumulate in the BLOOD, causing TOXIC effects on Brain function and Mental Retardation

- Treatment involves feeding a Synthetic diet limiting Branched-Chain Amino Acids (Val, Leu, Ile).

- In some forms of mild MSUD, the activity of the KCKD may be restored to normal by THIAMINE SUPPLEMENTATION of the diet!


Tetrahydrobiopterin/ Dihydrobiopterin

- Tetrahydrobiopterin (THB) is an essential cofactor in the HYDROXYLATIONS of the AROMATIC AMINO ACIDS, PHE, TYR, and TRP, as well as in the production of NITRIC OXIDE (NO) from ARG.

- It is biosynthesized from GTP via a pathway involving three enzymes and is regenerated by the reduced form of NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH)- dependent reduction of Dihydrobiopterin catalyzed by Dihydrobiopteridine Reductase

- Defects in the biosynthesis or regeneration of THB can lead to SECONDARY Phenylketonuria (PKU)

- The pathways for the production of MONAMINE Neurotransmitters (Dopamine, Norepinephrine, and Serotonin) from TYR and TRP are also disrupted when THB is Deficient, leading to NEUROLOGIC DYSFUNCTION

- Synthetic THB, Sapropterin is used in the treatment of Secondary PKU



- Defects in the activity of Phenylalanine Hydroxylase activity causes PHENYLKETONURIA (PKU), the most common inborn error of Amino Acid Metabolism

- PHE in these patients is instead converted to PHENYLPYRUVATE and then to Phenyllactate and to Phenylacetate.

- The latter two compounds disrupt Neurotransmission and block amino acid transport in the Brain as well as Myelin formation, resulting in severe impairment of Brian Function

- The patient's urine may have a MUSTY ODOR due to the Phenylacetate

- Synthesis of the pigment MELANIN, which is a by product of TYR, is also impaired

- This defect was the first one to be included in Newborn Screening for inherited metabolic disorders

- Treatment involved limiting PHE intake in infants

- Pregnant women with PKU also need to limit their PHE intake

- more than 80% of dietary protein for PKUY patient is supplied by a synthetic formula that is supplemented with TYR

- SECONDARY PKU is the result of a deficiency in TETRAHYDROBIOPTERIN (THB), which is an essential cofactor of Phenylalanine Hydroxylase

- Defects in either the synthesis or the regeneration of THB leads to SECONDARY PKU



- Tyrosinemia is characterized by ELEVATED Blood Levels of TYR

- Transient Tyrosinemia in newborns is the result of delayed expression of enzymes involved in the CATABOLISM of TYR

- Hereditary Infantile Tyrosinemia (Tyrosinemia Type I) is there result of a defect in the gene encoding FUMARYLACETOACETATE HYDROLASE, an enzyme in the pathway of TYR catabolism to FUMARATE

- Infants with this disorder have a distinctive CABBAGE-LIKE ODOR and develop SEVERE LIVER FAILURE unless promptly treated.

- They excrete SUCCINYLACETONE, a compound derive from Fumarylacetoacetate, in their Urine

- Succinylacetone is toxic to the LIVER and KIDNEYS

- It interferes with the TCA Cycle, causes Renal Tubule Dysfunction, and inhibits the Biosynthesis of HEME at the level of GAMMA- AMINOLEVULINIC ACID DEHYDRATES (Porphobilinogen Synthase)

- Tyrosinemia Type II is caused by a deficiency of Tyrosine AMINOTRANSFERASE, which generates P-HYDROXYPHENYLPYRUVATE from TYR

- Patients with this disorder exhibit PHOTOPHOBIA and skin lesions on their pals and Soles

- TYROSINEMIA TYPE III is the result of a defect in P-HYDROXYPHENYLPYRUVATE OXIDASE and is characterized by intermittent Ataxia.

- Of the three types of Tyrosinemia, Type I is the most common and used to require LIVER TRANSPLANTATION

- In recent times, NITISONE, a reversible inhibitor of P-HYDROXYPHENYLPYRUVATE OXIDASE



- Alkapeonuria is due to a defect in HOMOGENTISATE OXIDASE, an enzyme in the TYR degradative pathway

- It causes HOMOGENTISIC ACID to accumulate

- Autoxidation of Homogentisic Acid (with light) and Polymerization of products produce DARK-COLORED pigments in Urine

- Black pigmentation in the Intervertebral Disks of Patients with degenerative arthritis and Ochronosis (darkened Sclera) are also observed


Catecholamine degradation by MAO and COMT

- Catecholamines are short-lived signaling molecules.

- MONAMINE OXIDASE (MAO) and CATECHOL O- METHYLTRANSFERASE (COMT) are the enzymes involved in the degradation of Dopamine into HOMOVANILLIC ACID (HVA) and both Norepinephrine and Epinephrine into VANILLYLMANDELIC ACID (VMA)

- The levels of VMA in Urine are measured in patients suspected of having PHEOCHROMOCYTOMA

- In these patients, the Adrenal Glands OVERPRODUCE CATECHOLAMINES.

- MAO also converts Serotonin into 5-Hydroxyindoleacetic Acid, which is excreted in Urine

- MAO inhibitors such as Hydrazines, Phenethylamines, and Benzamides act as ANTIDEPRESSANTS due to their ability to inhibit RAPID DEGRADATION of Monamine Neurotransmitters in the Synaptic Cleft

- Some show higher specificity toward Dopamine Catabolism and are used to treat Parkinson Disease


Ammonia Toxicity

- Excess Ammonia, due to eitherr a disorder of the Urea Cycle or Liver Failure, can have highly toxic effects on the Brain and the CNS.

- Uncharged Ammonia (NH3), rather than Ammonium Ion (NH4+) is the toxic agent due to its ability to transverse biological membranes

- In addition to pH imbalance, Ammonia causes a swelling of ASTROCYTES in the Brain, leading to Cerebral Edema and Intracranial Hypertension

- The activity of the TCA Cycle is inhibited due to a depletion of ALPHA KETOGLUTARATE

- Postsynaptic excitatory potentials are inhibited, leading to a Depression of CNS function

- Depletion of GLU (Due to its conversion of GLN) results in disruption of its Neurotransmitter activity

- Ammonia also causes Mitochondrial Dysfunction



- Gout is a disorder characterized by HIGH levels of URIC ACID in the blood resulting from overproduction of Uric Acid ("primary Hyperuricemia") as in the Lesch-Nyhan Syndrome, or, more commonly, by under excretion of URIC ACID ("secondary hyperuricemia").

- Deposits of Sodium Urate in the joints of the extremities are exceedingly painful (gouty arthritis), and deposits in the kidney can cause Kidney damage

- Diets rich in purines (ex: Beans, lentils, spinach) together with meat, seafood, and alcohol may trigger episodes of gout

- Acidemia stimulates resorption of Uric Acid in the Kidney via the Urate transporter URAT1

- Treatment for Gout involves the use of drugs such as COLCHICINE that decreases the movement of Granulocytes to the affected areas and ALLOPURINOL that INHIBITS XANTHINE Oxidase and has been proposed to Increase the levels of the more soluble Purines HYPOXANTHINE and GUANINE


Uric Acid Levels as a Diagnostic marker for Gout

- Serum URIC ACID levels are diagnostic for Gout

- Normal serum Urate levels are 4.0 to 8.6 mg/dL in adult Males and 3.0 to 5.9 mg/dL in adult Females

- Urinary URATE levels are normally 9 mg/dL INCREASE the RISK of GOUT

- Urinary URATE levels are variable day to day and are most reliable when the patients are on a low PURINE DIET



- Persisten Hyperammonemia in newborns results from defects in any of the six enzymes (including NAG Synthase) associated with UREA CYCLE or in three distinct transporters (Mitochondrial Ornithine carrier, Mitochondrial enzymes lead to a more severe Hyperammonemia than those in the Systolic enzymes of the Ura Cycle

- A defect in ORNITHINE TRANSCARBOMOYLASE causes a Motichondrial buildup of Carbamoyl Phosphate, which then spills out into the Cytoplasm

- It can be metabolized by the Systolic Pyrimidine synthetic pathway to the intermediate, OROTIC ACID, which tends to accumulate and is excreted in the Urine (Orotic Acuduria) of male patients

- Management of the Urea Cycle defects involves limiting protein intake while ensuring adequate calorie consumption and the use of agents that can conjugate certain Amino Acids into excitable metabolites

- For example, Sodium Benzoate combines with Glycine to form Hippuric Acid, and Phenylacetate can conjugate Glutamine

- In some cases, the diet may be supplemented with CITRULLINE or ARGININE


Carbamoyl Phosphate Synthetase II (Cytosolic)

- The first step in de novo synthesis of Pyrimidines is catalyzed btw a CYTOSOLIC isoform of CARBAMOYL PHOSPHATE SYNTHETASE (CPS-II)

- Please not that this enzyme is different from the Mitochondrial version (CPS-I) that initiates the Urea Cycle

- CPS-II does not require N-acetylglutamate (NAG), but it is stimulated by PHOSPHORIBOSYL PYROPHOSPHATE (PRPP) and inhibited by URIDINE Triphosphate (UTP)

- Orotic Acid is an intermediate in the pathway for Synthesis of URIDINE MONOPHOSPHATE (UMP) from Cytosolic Carbamoyl Phosphate

- An AUTOSOMAL RECESSIVE defect in UMP SYNTHASE can lead to an accumulation of OROTIC ACID and result in OROTIC ACUDURIA

- However, unlike the case in ORNITHINE TRANSCARBAMOYLASE DEFICIENCY, OROTIC ACUDURIA due to defects in UMP Synthase is not accompanied by HYPERAMMONEMIA or a reduction in BLOOD UREA NITROGEN (BUN) levels


Direct and Indirect Bilirubin

- UNCONJUGATED BILIRUBIN is fairly INSOLUBLE in aqueous media while BILIRUBIN conjugated to GLUCORONATE is relatively soluble

- Soluble BILIRUBIN reacts with DIAZO REAGENT (p-Diazobensenesulfanilic Acid) to produce a pink to reddish-purple product which absorbs light at 540 nm (Direct Bilirubin)

- UNCONJUGATED Bilirubin can be made SOLUBLE in the presence of 50% METHANOL and can then react with DIAZO REAGENT (Indirect Bilirubin)

- Therefore, treating equal aliquots of Plasma or Serum samples with the Diazo reagent in the presence and absence of Methanol allows the measurement of TOTAL and DIRECT BILIRUBIN

- The difference between the two values would yield INDIRECT BILIRUBIN (Total- Direct = Indirect)

- An improvement to the assay involves replacing Methanol with a solution of Sodium Acetate and Caffeine-Benzoate

- Sodium Acetate provides an ALKALINE pH and Caffeine-Benzoate ACCELERATES the coupling of Unconjugated Bilirubin with the DIAZO Reagent, leading to the formation of a BLUE PRODUCT that absorbs at 600 nm

- Normal serum values of adults are 0.2 to 1.2 mg/dL for TOTAL BILIRUBIN and 0.1 to 0.3 mg/dL for DIRECT (CONJUGATED) Bilirubin

- Total Bilirubin levels in infants are in the range of 1 to 12 mg/dL with NEGLIGIBLE amounts of DIRECT BILIRUBIN!

****** UDP- GLUCURONYL TRANSFERASE!!!!!!!!!!!!!!************