Lecture 48

Question 1

What are metabolic defects in amino acid metabolism usually caused by?

Answer 1

1) Inborn errors of metabolism are commonly caused by mutant genes that generally result in abnormal proteins, most often enzymes
2) The inherited defects may be expressed as a total loss of enzyme activity or a partial deficiency in activity

Question 2

What is a treatment for metabolic defects in amino acid metabolism and what is important about the treatment?

Answer 2

1) Treatment: diets low in the amino acids whose catabolism is impaired
2) Newborn screening and timely initiation off treatment are essential. By law, all states must screen for over 20 disorders. All states screen for PKU

Question 3

What are common metabolic defects in amino acid metabolism?

Answer 3

Cystinuria, Histidinemia, Phenylketonuria, Methylmalonyl CoA mutase deficiency, & Albinism

Question 4

What are rare metabolic defects in amino acid metabolism?

Answer 4

Homocystinuria, Alkaptonuria, Maple syrup urine disease, Cystathioninuria, & Cystinosis

Question 5

What causes phenylketonuria (PKU)?

Answer 5

1) A deficiency in phenylalanine hydroxylase
2) The following reaction cannot occur:
L-phenylalanine + Tetrahydro-bioptern + O2 –> L-Tyrosine + Dihydro-biopterin + H2O (uses Phenylalanine hydroxylase)

Question 6

What are characteristics of phenylketonuria?

Answer 6

1) Most common clinically encountered inborn error of amino acid metabolism
2) Elevated levels of phenylalanine (10X normal), phenylpyruvate, phenyllactate, & phenylacetate in blood & urine
3) Symptoms: Hypopigmentation, due to inhibition of tyrosinase essential for melanin formation (patients often blond with fair skin & blue eyes)
4) CNS symptoms: intellectual disability by age one, developmental delay, microcephaly, & seizures in untreated PKU patients (now rare due to prenatal testing)
5) Treatment: dietary restriction of Phe

Question 7

What does phenylalanine normally form?

Answer 7

1) Phenylalanine is normally converted to Tyrosine

2) Tyrosine can be used to produce tissue proteins, melanin, catecholamines, fumarate & acetoacetate

Question 8

What does phenyalanine form in phenylketonuria?

Answer 8

1) Phenylalanine is converted to Phenylpyruvate

2) Phenylpyruvate is converted to phenyllactate & phenylacetate

Question 9

What can hyperphenylalanemia be caused by?

Answer 9

1) May be caused by deficiencies in any of the several enzymes required to synthesize Tetrahydrobioptern (BH4) or in dihydropteridine reductase, which regenerates BH4 from BH2
2) These enzymes are used in Tyrosine synthesis, catecholamine synthesis, & serotonin synthesis
3) A deficiency in dihydropteridine reductase or any of the enzymes of BH4 synthesis leads to hyperphenyalanemia and decreased synthesis of catecholamines & serotonin

Question 10

What is the inheritance pattern of maple syrup urine disease (MSUD)?

Answer 10

1) Autosomal recessive

Question 11

What causes maple syrup urine disease (MSUD)?

Answer 11

1) Partial or complete deficiency in mitochondrial branched chain alpha-keto acid dehydrogenase (BCKD), that oxidatively decarboxylates Leu, Ile, & Val
2) These BCAAs and their corresponding alpha-keto acids accumulate in blood, casing interference with brain functions (especially Leu & alpha-Kic acid)

Question 12

What are symptoms of maple syrup urine disease (MSUD)?

Answer 12

1) A characteristic maple syrup odor to the urine due to rise in Ile
2) Feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma
3) If untreated, disease is fatal
4) If treatment is delayed, intellectual disability results

Question 13

How is maple syrup urine disease (MSUD) treated?

Answer 13

Synthetic formula free of BCAAs supplmeneted with limited amount of Leu, Ile, & Val to allow normal growth & development without producing toxic levels

Question 14

What causes albinism?

Answer 14

Results from an absent or defective copper-requiring tyrosinase deficiency

Question 15

What is the inheritance pattern for albinism?

Answer 15

Albinism appears in different forms: autosomal recessive inheritance is primary mode

Question 16

What are the symptoms of albinism?

Answer 16

1) White hair, pink eyes, & hypopigmented pale skin
2) Sensitive to sunlight (easy to sunburn and increased skin cancer)
3) Impaired vision & photophobia

Question 17

How is albinism treated?

Answer 17

Protection from UV exposure

Question 18

How is eumelanin formed from tyrosine?

Answer 18

1) Tyrosine –> DOPA (uses tyrosinase)
2) DOPA –> DOPAquinone (uses tyrosinase)
3) Series of steps leads to eumelanin

Question 19

How is pheomelanin formed from tyrosine?

Answer 19

1) Tyrosine –> DOPA (uses tyrosinase)
2) DOPA –> DOPAquinone (uses tyrosinase)
3) DOPAquinone + cysteine –> CysteinylDOPA
4) CysteinylDOPA –> 1,4-benzothiazinyl-alanine
5) Pheomelanin

Question 20

What is melanin?

Answer 20

1) In humans, melanin is the primary determinant of skin color
2) Melanin is also found in hair, the pigmented tissue underlying the iris of the eye, & the stria vascularis of the inner ear
3) In the brain, tissues with melanin include pigment-bearing neurons within areas of the brainstem, such as the locus coeruleus and the substantia nigra

Question 21

How is melanin formed?

Answer 21

1) Melanin in the skin is produced by melanocytes, which are found in the basal layer of the epidermis
2) Albinism results from very little or no melanin synthesis in the body

Question 22

What are two types of melanin?

Answer 22

Pheomelanin & eumelanin are found in human skin & hair, but eumelanin is the most abundant melanin in humans

Question 23

What is eumelanin?

Answer 23

1) Eumelanin polymers are composed of numerous cross-linked 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) polymers
2) Two types are recognized: black & brown
3) A small amount of black eumelanin in the absence of other pigments causes grey hair
4) A small amount of brown eumelanin in the absence of other pigments results in blond hair

Question 24

What is pheomelanin?

Answer 24

1) Pheomelanin imparts a pink to red hue and, thus, is found in particularly large quantities in red hair
2) Pheomelanin is particularly concentrated in the lips, nipples, glans of the penis, & vagina
3) In chemical terms, pheomelanin differs from eumelanin in that its oligomer structure incorporates benzothiazine and benzothiazole units that are produced, instead of DHI & DHICA from tyrosine and cysteine

Question 25

What is homocystininuria?

Answer 25

1) Group of rare disorder involving defects in metabolism of homocysteine (Hcy)
2) Patients exhibit lens dislocation, skeletal abnormalities (long limbs & fingers), intellectual disability, increased risk for developing blood clots
3) Treatment includes restriction of methionine and supplementation with vitamins B6, B12, & folate

Question 26

What is homocystinuria characterized by?

Answer 26

High plasma and urinary levels of Hcy & methionine

Question 27

What is alkaptonuria?

Answer 27

A rare non-fatal metabolic condition involving a deficiency in homogentisic acid oxidase, resulting in the accumulation of homogentisic acid (HA)-((2,5-dihydroxyphenyl) acetic acid), an intermediate in the degradative pathway of tyrosine

Question 28

What are symptoms of alkaptonuria?

Answer 28

1) Homogentisic aciduria (the HA in urine oxidizes to a dark pigment on standing)
2) Large joint arthritis that can be severely crippling
3) Deposition of black pigment in cartilage & collagenous tissue

Question 29

What is a treatment for alkaptonuria?

Answer 29

Diets low in Phe & Tyr reduce the levels of HA and decrease the amount of pigment deposited in body tissues

Question 30

How is Nitric oxide synthesized?

Answer 30

L-Arginine + NADPH + H+ –> L-citrulline+ NO + NADP+ (use of NO synthase (NOS))

Question 31

What are 3 types of nitric oxide synthases?

Answer 31

1) Endothelial (eNOS)
2) Neural (nNOS)
3) Inducible (iNOS)

Question 32

What are coenzymes of nitric oxide synthases?

Answer 32

1) FMN
2) FAD
3) Heme
4) Tetrahydrobiopterin
5) Ca2+-calmodulin (only for eNOS *& nNOS)

Question 33

How is erectile dysfunction treated?

Answer 33

1) The blood vessels in the corpora cavernosa of the penis are expected to dilate profoundly in response to parasympathetic nerve stimulation, with NO being the most important mediator
2) In this tissue, NO is formed mainly in the nerve terminals and only to a lesser extent in the vascular endothelium
3) As in other vascular beds, however, NO acts by stimulating the soluble guanylate cyclase in vascular smooth muscle
4) Erectile dysfunction (impotence) is treated with slidenafil (Viagra) and related drugs that inhibit phosphodiesterase-5
5) This cGMP-specific phosphodiesterase is responsible for the degradation of cGMP in the vascular smooth muscle of the penis

Question 34

What are functions of nitric oxide?

Answer 34

1) Relaxes smooth muscle
2) Prevents platelet aggregation
3) Functions as a neurotransmitter in the brain
4) Mediates tumoricidal and bactericidal actions of macrophages

Question 35

What is the Ca2+/NO & NO/cGMP pathway to relaxing arterial smooth muscle?

Answer 35

1) Acetylcholine acts on acetylcholine GPCR
2) Acetylcholine GPCR activates Phospholipase C
3) Phopholipase C release IP3 to activate Ca2+-calmodulin
4) Ca2+-calmodulin activates NO synthase
5) NO synthase converts argnine + O2 –> Citrulline + NO
6) NO activates the NO receptor in smooth muscle cells to convert GTP to cGMP & pyrophosphate
7) cGMP activates protein kinase G
8) Protein kinase G relaxes smooth muscle cells