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.
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
3
Q
Tetrahydrobiopterin (BH4)
A
- Coenzyme required for ring hydroxylation reactions (e.g., phenylalanine to tyrosine)
- important for the synthesis of tyrosine and neurotransmitters
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
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
6
Q
whats formed when
phenylalanine
tyrosine
are all degraded?
A
they form fumarate
this then goes into the citric acid cycle
7
Q
whats formed when
asparagine
aspartate
are all degraded?
A
they form oxaloacetate
this then goes into the citric acid cycle
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
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
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)
11
Q
a-ketoglutarate breakdown yields which aa?
A
- glutamate
- glutamine
- arginine
- proline
12
Q
Succinyl-Co-A degradation yields which aa?
A
- isoleucine
- threonine
- methionine
- valine
I think my vagina succs
13
Q
degradation of fumarate forms which aa?
A
- phenylalanine
- tyrosine
14
Q
which aa are used for oxaloacetate
A
- asparagine
- aspartate
- methionine
- threonine
- lysine
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.
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.
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)
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.
- 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.
19
Q
which enzymes are “brached chain amino acids”
A
valine
isoleucine
leucine
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.
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
22
Q
to make amino acids, where do the carbon skeleton precursors some from?
A
- glycolysis
- citric acid cycle
- pentose phosphate pathways
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.
24
Q
amino acid biosynthesis from glycolysis
A
3-phophoglycerate
- serine
- glycine
- cysteine
phsphoenolpyruvate
- tryptophan
- phenylalanine
- tyrosine
pyruvate -alanine -valine -leucine isoleucine
25
amino acid biosynthesis from citric acid cycle
oxaloacetate
- aspartate
- -asparagine
- -methionine
- -threonine
- -lysine
a-ketoglutarate
- glutamate
- -glutamine
- -proline
- -arginine
26
pentose phosphate pathway
erythrose 4-phosphate
- tryptophan
- phenylalanine
- tyrosine
ribose 5-phosphate
-histidine
27
histamine vs histadine
histamine is a catabolite of histidine
28
Overview of one-carbon metabolism
- 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
Major players in one-carbon metabolism
- Tetrahydrofolate (THF, FH4)
- Vitamin B12
- S-adenosylmethionine (SAM)
30
Tetrahydrofolate (THF, FH4)
- produced from vitamin folate
| - primary one-carbon carrier in the body
31
vitamin B12
- 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
S-adenosylmethionine (SAM)
-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
define the term folate
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
relationship of Folate and SAM pathways
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
methotrexate
inhibits dihydrofolate reductase
36
Folate conversion to tetrahydrofolate
-folate (Vitamin B9)
Dihydrofolate reductase
- Two step reaction
- Inhibited by Methotrexate (ultimately interferes with DNA synthesis)
-Active form: Tetrahydrofolate (THF)
37
Folate cycle
-THF carries one-carbon units
Sources of one-carbon units
- serine (major source)
- histidine
- formaldehyde
- formate
38
SAM Cycle
- 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
pyrimidine synthesis
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
Purine Synthesis
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
tryptophan-derivatives
- serotonin (neurotransmitter)
- melatonin (neurotransmitter)
- niacin (NAD, NADP precursor)
42
Serotonin
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
Melatonin
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
Niacin (Nicotinate)
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
tyrosine-derived neurotransmitters
- 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
Dopamine
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
Norepinephrine and Epinephrine
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
Melanins
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
Thyroid Hormones (T3, T4)
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
GABA and Histamine
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
Creatine
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
Glutathione
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
Nitric Oxide
Synthesized from Arginine
Synthesis
- Enzyme: Nitric oxide synthase
- Cofactors
- --Tetrahydrobiopterin
- ----Non-Classical PKU require pharmacological doses
- --NADPH
Properties
- Vasodilator
- Antibacterial
- Neurotransmitter
54
a patient lacking skin pigmentation is sensitive to sunlight. this individual lacks enzyme necessary to convert what amino acid to melanin?
Tyrosine
55
Maple Syrup Urine Disease
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
Phenylalanine/Tyrosine Related Diseases
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
Phenylketonuria (PKU)-- Classical
*NOTE: This will DEFINITELY be on the exam!!!
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
Types of PKU (Classical) Treatment
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
PKU-Non-classical
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
Tyrosinemia I
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
Tyrosinemia II
Deficiency: Tyrosine Aminotransferase
- Cofactor: Pyridoxal Phosphate
- Very rare
- Erosions hands and feet
- Treatment: low tyrosine diet
62
Tyrosinemia III
Deficiency: p-Hydroxyphenylpyruvate dioxygenase
-Enzyme Cofactor: Ascorbate (Vitamin C)
- Very common
- Benign
63
Alkaptonuria
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
Megaloblastic anemia
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
Homocystinuria
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
pyruvate breakdown yields what AAs?
- alanine
- valine
- leucine
- isolecine
67
3-phosphoglycerate breakdown yields what aa?
glycine
serine
cysteine
68
ribulose 5-phosphate breakdown yields what AAs?
histidine
69
PEP/erythrose 4-phsophate breakdown yields what aas?
threonine
tryptophan
phenylalanine
