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MTC Block 2: Post Quiz Material > 6- Amino Acid Metabolism II > Flashcards

6- Amino Acid Metabolism II Flashcards

1
Q

Pyridoxal Phosphate (PLP)

A
  • The quintessential coenzyme of amino acid metabolism
  • Derived from vitamin B6

In degradation

  • involved in removal of amino groups through transamination reactions
  • involved in donation of amino groups for various amino acid biosynthetic pathways.
  • Is involved in degradation of ALL of the common amino acids (except threonine, lysine, proline, and hydroxyproline)
  • It is also required for certain reactions that involve the carbon skeleton of amino acids.
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2
Q

Tetrahydrofolate (THF, FH4)

A
  • Coenzyme used to transfer one-carbon groups at various oxidation states (accept or donate a one-carbon group).
  • FH4 is used in both amino acid degradation (e.g., serine and histidine) and biosynthesis (e.g., glycine)
  • Folate – most oxidized form
  • FH4 – most reduced form
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3
Q

Tetrahydrobiopterin (BH4)

A
  • Coenzyme required for ring hydroxylation reactions (e.g., phenylalanine to tyrosine)
  • important for the synthesis of tyrosine and neurotransmitters
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4
Q 
whats formed when arginine 
glutamine 
histidine
proline
are all degraded?
A

they form glutamate which is turned into a-ketoglutarate

this then goes into the citric acid cycle

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5
Q 
whats formed when 
isoleucine
methionine 
threonine 
valine
are all degraded?
A

they form succinyl-CoA

this then goes into the citric acid cycle

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6
Q

whats formed when
phenylalanine
tyrosine
are all degraded?

A

they form fumarate

this then goes into the citric acid cycle

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7
Q

whats formed when
asparagine
aspartate
are all degraded?

A

they form oxaloacetate

this then goes into the citric acid cycle

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8
Q 
whats formed when alanine
cysteine
glycine
serine
threonine
tryptophan 
are all degraded?
A

they form pyruvate which (when combined with CO2) is converted into oxaloacetate
-this then goes into the citric acid cycle

pyruvate can also be converted into acetyl-Co-A which can form citrate (to go into the tca cycle)
-the pyruvate can also form ketone bodies

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9
Q 
whats formed when isoleucine 
leucine
threonine
tryptophan 
are all degraded?
A

they form acetyl-CoA which can form citrate
-this then goes into the citric acid cycle

-ketone bodies can also be formed from acetyl-CoA

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10
Q 
whats formed when 
leucine 
lysine
phenylalanine 
tryptophan 
tyrosine
are all degraded?
A

they form acetoacetyl-CoA

-this can either be converted into ketone bodies or acetyl Co-A (this can then be converted into citrate for the tca cycle)

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11
Q

a-ketoglutarate breakdown yields which aa?

A
  • glutamate
  • glutamine
  • arginine
  • proline
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12
Q

Succinyl-Co-A degradation yields which aa?

A
  • isoleucine
  • threonine
  • methionine
  • valine

I think my vagina succs

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13
Q

degradation of fumarate forms which aa?

A
  • phenylalanine

- tyrosine

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14
Q

which aa are used for oxaloacetate

A
  • asparagine
  • aspartate
  • methionine
  • threonine
  • lysine
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15
Q

what it means to be glucogenic

A
  • Amino acids whose catabolism yields pyruvate or one of the intermediates of the TCA cycle are termed glucogenic.
  • Because these intermediates are substrates for gluconeogenesis, they can give rise to the net synthesis of glucose in the liver and kidney.
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16
Q

what it means to be ketogenic

A
  • Amino acids whose catabolism yields either acetoacetate or one of its precursors (acetyl CoA or acetoacetyl CoA) are termed ketogenic.
  • Leucine and lysine are the only exclusively ketogenic amino acids found in proteins.

• Their carbon skeletons are not substrates for gluconeogenesis and, therefore, cannot
give rise to the net synthesis of glucose.

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17
Q

phenylalanine and tyrosine degradation

A

1st step
Enzyme = Phenylalanine hydroxylase
Cofactor = Tetrahydrobiopterin (Regenerated by Dihydrobiopterin Reductase)

  • Phenylalanine is converted to tyrosine, which undergoes oxidative degradation.
  • The last step in the pathway produces both fumarate and the ketone body acetoacetate.
  • Deficiencies of different enzymes in the pathway result in phenylketonuria, tyrosinemia, and alcaptonuria.
  • Some of these components have alternative names (4HPP is same as p-Hydroxyphenylpyruvate)
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18
Q

methionine catabolism

A
  • Methionine is converted to S- adenosylmethionine (SAM), the major methyl group donor in one-carbon metabolism (enzyme: methionine adenosyltransferase)
  • cysteine is the product OR more methionine and tetrahydrofolate
  • SAM –> SAH –> Homocysteine

2 homocysteine disposal pathways

1.Methionine can be regenerated from homocysteine by a reaction that requires both FH4 and vitamin B12.

  1. Homocysteine can provide the sulfur needed for the synthesis of cysteine.
    - –Carbons of homocysteine are then metabolized to α-ketobutyrate, which undergoes oxidative decarboxylation to propionyl-CoA.
    - –The propionyl-CoA is then converted to succinyl-CoA.
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19
Q

which enzymes are “brached chain amino acids”

A

valine
isoleucine
leucine

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20
Q

degradation of branched chain amino acids

A
  • The same enzymes are used for the first two steps for isoleucine, leucine, and valine.
  • The transamination is by Pyroxidal Phosphate (PLP) (Vitamin B6)
A multistep process is catalyzed by
the mitochondrial branched-chain α-keto acid dehydrogenase complex. This requires
---Thiamine (Vitamin B1)
---Pantothenic acid (Vitamin B5) 
---Niacin (Vitamin B3)
---Riboflavin (Vitamin B2)

-Degradation occurs at low levels in the mitochondria of most tissues, but the muscle carries out the highest level of branched-chain amino acid oxidation.

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21
Q

a newborn infant has elevated levels of phenylalanine and phenylpyruvate in her blood, which enzyme might be deficient in the baby?

A

dihydrobiopteridin reductase

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22
Q

to make amino acids, where do the carbon skeleton precursors some from?

A
  • glycolysis
  • citric acid cycle
  • pentose phosphate pathways
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23
Q

amino acid biosynthesis

A
  • The carbons of 10 amino acids may be produced from glucose through intermediates of glycolysis or the TCA cycle.
  • The 11th nonessential amino acid, tyrosine, is synthesized by hydroxylation of the essential amino acid phenylalanine.
  • Only the sulfur of cysteine comes from the essential amino acid methionine; its carbons and nitrogen come from serine.
  • transamination (TA) reactions involve pyridoxal phosphate (PLP) and another amino acid/α-keto acid pair.
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24
Q

amino acid biosynthesis from glycolysis

A

3-phophoglycerate

  • serine
  • glycine
  • cysteine

phsphoenolpyruvate

  • tryptophan
  • phenylalanine
  • tyrosine
pyruvate 
-alanine 
-valine
-leucine
isoleucine
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25
Q

amino acid biosynthesis from citric acid cycle

A

oxaloacetate

  • aspartate
  • -asparagine
  • -methionine
  • -threonine
  • -lysine

a-ketoglutarate

  • glutamate
  • -glutamine
  • -proline
  • -arginine
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26
Q

pentose phosphate pathway

A

erythrose 4-phosphate

  • tryptophan
  • phenylalanine
  • tyrosine

ribose 5-phosphate
-histidine

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27
Q

histamine vs histadine

A

histamine is a catabolite of histidine

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28
Q

Overview of one-carbon metabolism

A
  • Some synthetic pathways require the addition of single-carbon groups that exist in a variety of oxidation states, including formyl, methenyl, methylene, and methyl.
  • The “one-carbon pool” refers to the single-carbon units attached to this group of carriers.
  • One-carbon groups are transferred by reactions involving tetrahydrofolate (FH4), vitamin B12, and S-adenosylmethionine (SAM).
29
Q

Major players in one-carbon metabolism

A
  • Tetrahydrofolate (THF, FH4)
  • Vitamin B12
  • S-adenosylmethionine (SAM)
30
Q

Tetrahydrofolate (THF, FH4)

A
  • produced from vitamin folate

- primary one-carbon carrier in the body

31
Q

vitamin B12

A
  • involved in 2 reactions in the body
    1. Transfers a methyl group, obtained from FH4, to homocysteine, forming methionine.

(less important to remember this one)
2. rearrangement of the methyl group of l-methylmalonyl coenzyme A (l-
methylmalonyl-CoA) to form succinyl-CoA

32
Q

S-adenosylmethionine (SAM)

A

-produced from methionine and adenosine triphosphate (ATP)

-transfers the methyl group to precursors that form several compounds,
including creatine, phosphatidylcholine, epinephrine, melatonin, methylated nucleotides, and methylated DNA

33
Q

define the term folate

A

The term “folate” is used to represent a water-soluble B-complex vitamin that functions in transferring single-carbon groups at various stages of oxidation.

34
Q

relationship of Folate and SAM pathways

A

Folate

  • Purine Synthesis
  • Required for thymidylate synthetase for conversion of deoxyuridyl monophosphate (dUMP) to deoxythymidylate monophosphate (dTMP) for DNA synthesis
  • Synthesis of methionine for SAM pathway

SAM

  • methyl donation via methyltransferases
  • DNA methylation
  • mRNA methylation
35
Q

methotrexate

A

inhibits dihydrofolate reductase

36
Q

Folate conversion to tetrahydrofolate

A

-folate (Vitamin B9)

Dihydrofolate reductase

  • Two step reaction
  • Inhibited by Methotrexate (ultimately interferes with DNA synthesis)

-Active form: Tetrahydrofolate (THF)

37
Q

Folate cycle

A

-THF carries one-carbon units

Sources of one-carbon units

  • serine (major source)
  • histidine
  • formaldehyde
  • formate
38
Q

SAM Cycle

A
  • Methionine adenosyl-transferase catalyzes formation of S-adenosylmethionine
  • Methyl group on SAM donated to multiple molecules by methyl transferases
  • S-adenosylhomocysteine is recycled back to homocysteine

Major Enzyme: Methionine synthase

  • N5-Methyltetrahydrofolate donates a one carbon unit to fuel the SAM cycle
  • Methyl group transferred onto vitamin B12 and then to homocysteine
  • Methionine formed for SAM pathway (no net methionine synthesized)
Neural Tube Defects
Caused by deficiencies of
-methionine synthase 
-Folate
-Vitamin B12

-Incidence decreased by fortification of grains with folate

39
Q

pyrimidine synthesis

A

Generated from

  • Aspartate (carbons)
  • Glutamine (nitrogen)

Major enzyme: Thymidylate synthase

  • conversion of dUMP to dTMP
  • inhibited by 5-flurouracil derivative (FdUMP)
  • Requires Tetrahydrogolate reductase
  • -product dihydrofolate reduced by dihydrofolate reductase
  • -Methotrexate inhibits dihydrofolate reductase (which reduces THF, so consider effects for neural tube if pregnant)
40
Q

Purine Synthesis

A

Generated from

  • aspartate
  • glycine
  • glutamine
  • formyl-tetra-hydrofolate

-Folate is essential cofactor int he synthesis of inosine monophosphate (IMP)

IMP: all purines are derived from this

41
Q

tryptophan-derivatives

A
  • serotonin (neurotransmitter)
  • melatonin (neurotransmitter)
  • niacin (NAD, NADP precursor)
42
Q

Serotonin

A

Synthesized from Tryptophan

Synthesis

  • tryptophan hydroxylase
  • Requires tetrahydrobiopterin
  • Forms dihydrobiopterin
  • Dihydrobiopterin reductase
  • –Deficient in Non-Classical PKU
  • Aromatic amino acid decarboxylase
  • –Requires PLP

Properties

  • Neurotransmitter and hormone
  • Mood
  • Sleep
  • appetite
  • intestinal movements
43
Q

Melatonin

A

Synthesized from Tryptophan

Synthesis

  • Synthesized by pineal gland in response to light sensed by the retinal ganglion cells
  • Uses S-adenosylmethionine (SAM)

Properties

  • Endocrine hormone that controls
  • Circadian rhythm
  • Menstrual cycle
  • Powerful antioxidant.
44
Q

Niacin (Nicotinate)

A

Synthesized from Tryptophan

Synthesis

  • Multiple step reaction
  • Requires multiple vitamins
  • –Riboflavin (Vitamin B2 for flavin adenine dinucleotide (FAD)
  • –Pyridoxine (Vitamin B6) for pyridoxal phosphate (PLP)
  • –Thiamin (Vitamin B1) for thiamin pyrophosphate (TPP)

Properties

  • Vitamin B3
  • Also known as nicotinic acid
  • Precursor to NAD and NADP
45
Q

tyrosine-derived neurotransmitters

A
  • Dopamine
  • norepinephrine (NE)
  • epinephrine/adrenaline

*are biologically active (biogenic) amines that are collectively termed catecholamines

  • Dopamine and NE are synthesized in the brain and function as neurotransmitters.
  • Epinephrine is synthesized from NE in the adrenal medulla.
46
Q

Dopamine

A

Synthesized from Tyrosine

Synthesis

  • Enzyme: Tyrosine hydroxylase
  • -Requires tetrahydrobiopterin
  • -Forms dihydrobiopterin
  • -Dihydrobiopterin reductase
  • –Deficient in Non-Classical PKU
  • Enzyme: Aromatic amino acid decarboxylase
  • -Requires PLP

Parkinson’s Disease

  • Destruction of cells in the substantia nigra
  • Decreased synthesis of dopamine
  • Symptoms
  • -Resting tremors
  • -Slow or no movement
  • -Rigidity of joints
  • -Stooped, slow walking
47
Q

Norepinephrine and Epinephrine

A

Synthesized from Tyrosine

Norepinephrine

  • Synthesis
  • -Dopamine β-hydroxylase
  • –Requires ascorbate (Vitamin C)

Properties
-Important for focusing brain, heart rate, metabolism
of fats and muscle function

Epinephrine

  • Synthesis
  • -Phenylethanolamine-N-methyltransferase
  • –Requires S-adenosylmethionine
  • Properties
  • -Stimulates metabolism for energy production cAMP production, gluconeogenesis, glycogen lysis
  • -Vasodilation
48
Q

Melanins

A

Synthesized from Tyrosine

Major Enzyme: Tyrosinase

  • Required for synthesis of melanin pigments in iris, retina, hair and skin
  • Deficiency – Albinism
  • -~ 1:1700
  • -Sun sensitivity
  • -Skin cancer
  • -Vision loss
  • -Autosomal recessive
49
Q

Thyroid Hormones (T3, T4)

A

Synthesized from Tyrosine

Synthesis

  • Thyroglobulin is a protein, source of tyrosine
  • tyrosine covalently bound to iodine (iodination)
  • essentially, two tyrosines linked together with additon of iodine at 3 or 4 positions on the ring (position = name)

Properties

  • bind to nuclear receptors
  • regulate expression of genes involved in
  • -Mobilization and oxidization of fats
  • -Gluconeogenesis
  • -Glycogenolysis
  • -Brain development
  • -Growth
50
Q

GABA and Histamine

A

Both required specific decarboxylases
-Require PLP (Vitamin B6)

GABA

  • Synthesized from Glutamate
  • Inhibitory neurotransmitter
  • Deficiency
  • —Seizures

Histamine

  • synthesized from Histidine
  • Neurotransmitter
  • Stimulates
  • —HCl secretion in stomach
  • —Allergic reaction: vasodilation and influx of inflammatory cells
  • —smooth muscle contraction in stomach, lungs, uterus
51
Q

Creatine

A

Generated from

  • glycine
  • arginine
  • S-Adenosylmethionine (SAM)
  • Guanidinoacetate is formed in the kidney from arginine and glycine
  • synthesized in the liver by methylation of guanidinoacetate using SAM as the methyl donor
  • creatine is used to recycle ATP
52
Q

Glutathione

A

Synthesized from Glutamate

Synthesis

  • Glutathione synthesis
  • –γ-Glutamyl cysteine synthetase (GCS) – rate-limiting
  • –Glutathione synthetase

Properties
-Glutathione (GSH) is a tripeptide composed of
glutamate, cysteine, and glycine that has numerous important functions within cells.
-GSH = Active form = reduced
-Oxidized form is reduced by glutathionine reductase using
NADPH from hexose monophosphate shunt

Function

  • Antioxidant
  • Cofactor – Reducing agent
  • Disulfuide bond rearrangements
  • Can be conjugated to drugs to make them more water soluble
53
Q

Nitric Oxide

A

Synthesized from Arginine

Synthesis

  • Enzyme: Nitric oxide synthase
  • Cofactors
  • –Tetrahydrobiopterin
  • —-Non-Classical PKU require pharmacological doses
  • –NADPH

Properties

  • Vasodilator
  • Antibacterial
  • Neurotransmitter
54
Q

a patient lacking skin pigmentation is sensitive to sunlight. this individual lacks enzyme necessary to convert what amino acid to melanin?

A

Tyrosine

55
Q

Maple Syrup Urine Disease

A

Deficiency: Branched Chain α-keto acid dehydrogenase (BCKD)

  • Typically rare ~ 1:180,000,
  • Higher (1:176) in selected populations
  • Urine characteristic sweet odor
  • Severity depends on the mutation
  • Included in newborn screening

Can cause

  • Mental retardation
  • Death (within first few weeks if not diagnosed)

Treatment

  • Low Protein Diet
  • Thiamin (Vitamin B1)
56
Q

Phenylalanine/Tyrosine Related Diseases

A

Inherited deficiencies in the enzymes of phenylalanine and tyrosine metabolism lead to the diseases:

  • Phenylketonuria (PKU)
  • Tyrosinemia I, II, III
  • Alkaptonuria
  • Condition of albinism
57
Q

Phenylketonuria (PKU)– Classical

*NOTE: This will DEFINITELY be on the exam!!!

A

Deficiency: Phenylalanine hydroxylase

  • Most common inborn error of amino acid metabolism
  • ~1:10,000
  • Autosomal recessive
  • included in newborn screening

Without treatment

  • Intellectual deficits
  • Growth retardation
  • Seizures
  • Fair skin, eczema
  • Musty body odor

With treatment
-Normal life

58
Q

Types of PKU (Classical) Treatment

A
  1. Low phenylalanine diet
    - For life
    - If pregnant – this is required for normal baby! -Baby without diet
    - —Microcephaly
    - —Intellectual disabilities
    - —Congenital heart defects
  2. Amino acid supplement without phenylalanine
  3. Kuvan (Tetrahydrobiopterin) – required for tyrosine hydroxylase and tryptophan hydroxylase
59
Q

PKU-Non-classical

A

Deficiency: dihydrobiopterin reductase

  • Rare
  • ~1:1,000,000

Treatment
1. Low phenylalanine diet – for life
2. Amino acid supplement without phenylalanine
3. Kuvan (Tetrahydrobiopterin) – required for tyrosine
hydroxylase and tryptophan hydroxylase
4. L-dopa for dopamine, norepinephrine and epinephrine
5. 5-hydroxytryptophan for serotonin and melatonin

60
Q

Tyrosinemia I

A

Deficiency: Fumarylacetoacetase

Normally:

  • Fumarate enters the Citric Acid Cycle
  • Acetoacetate converted to ketone bodies or Acetyl-CoA

Deficiency
-~1:100,000

-If not treated, death by 2 years of age

Treatment

  1. NTBC
    - –2-(2-nitro-4-trifluoromethylbenzoyl)-1,3- cyclohexanedione (NTBC)
    - –NTBC treatment of Tyrosinemia I shifts the metabolic block from FAA hydrolase to 4HPP dioxygenase
  2. Liver transplant
61
Q

Tyrosinemia II

A

Deficiency: Tyrosine Aminotransferase

  • Cofactor: Pyridoxal Phosphate
  • Very rare
  • Erosions hands and feet
  • Treatment: low tyrosine diet
62
Q

Tyrosinemia III

A

Deficiency: p-Hydroxyphenylpyruvate dioxygenase

-Enzyme Cofactor: Ascorbate (Vitamin C)

  • Very common
  • Benign
63
Q

Alkaptonuria

A

Deficiency: Homogentisate 1,2 dioxygenase

-Enzyme Cofactor: Ascorbate (Vitamin C)

  • 1:200,000
  • Homogentisate (HGA) excreted in urine
  • In presence of oxygen forms black complexes
  • –Urine
  • –Deposits in soft tissues
  • –Deposits in joints: arthritis and disc calcification
64
Q

Megaloblastic anemia

A

Deficiency:

  • Thymidylate synthase deficiency
  • Folate deficiency
  • Vitamin B12 deficiency
  • Decline in production of mature red blood cells, build up of immature cells, large cells (macrocytes)
  • Impaired DNA synthesis

Affected:

  • Strict vegetarians: Vitamin B12 is not in plants
  • Defect in intestinal absorption of Vitamin B12

Symptoms:

  • anemia
  • neurological disorders
65
Q

Homocystinuria

A

Normally:

  • Methionine is degraded to homocysteine
  • Homocysteine converted to Cysteine —Cystathionine β-synthase
  • –Cystathionine β-lyase

Homocystinuria caused by deficiencies

  • Cystathionine β-synthase-Severe
  • –intellectual disability, tall stature, osteoporosis, kyphosis (curvature of the spine), lens displacement, thrombosis and atherosclerosis, stroke and myocardial infarction.
  • Cystathionine β-lyase -PLP deficiency
  • Vitamin B12
  • Folate
  • Methionine synthase
66
Q

pyruvate breakdown yields what AAs?

A
  • alanine
  • valine
  • leucine
  • isolecine
67
Q

3-phosphoglycerate breakdown yields what aa?

A

glycine
serine
cysteine

68
Q

ribulose 5-phosphate breakdown yields what AAs?

A

histidine

69
Q

PEP/erythrose 4-phsophate breakdown yields what aas?

A

threonine
tryptophan
phenylalanine

MTC Block 2: Post Quiz Material (7 decks)

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