Amino acids Flashcards
What 2 amino acids are purely ketogenic?
- Leucine
- Lysine
All amino acids except from one have both L and D configurations. What amino acid only has one configuration?
Glycine
What are the 2 main basic amino acids - have a positive charge?
- Arginine (most basic)
- Lysine
- Also histidine, although only slightly so has no net charge at plasma pH
What 2 amino acids are found in histones, which give them a positive charge?
- Arginine
- Lysine
What are the 2 main acdic amino acids, have a negative charge as they donate H+ ions making solutions more acidic?
- Aspartate
- Glutamate
What type of amino acids are commonly found in the lipid bilayer of cell membranes?
Hydrophobic
What amino acids are swapped in sickle cell anemia?
Hydrophilic glutamate substituted for nonpolar/hydrophobic valine
What amino acid has a rigid structure and is found in collagen?
Proline
Are most amino acids glucogenic or ketogenic?
- Glucogenic OR glucogenic and ketogenic
What can ketogenic amino acids not become?
Glucose
What are ketogenic amino acids converted into?
Acetyl CoA
What 2 amino acids are purely ketogenic?
- Lysine
- Leucine
Both essential
What is the 1st step in phenylalanine metabolism?
Phenylalanine
-> Tyrosine
Enzyme: Phenylalanine Hydroxylase
What substance acts as a cofactor for phenylalanine hydroxylase?
Tetrahydrobiopterin (BH4)
What does Tetrahydrobiopterin lose and become when converting Phenylalanine into Tyrosine?
Dihydrobiopterin (BH2)
- Loses 2 Hs
What enzyme and molecule converts Dihydrobiopterin (BH2) back to Tetrahydrobiopterin (BH4)?
Dihydrobiopteridine Reductase
- NADH
What enzyme converts Phenylalanine
-> Tyrosine?
Phenylalanine hydroxylase
What is classic PKU due to?
Phenylalanine hydroxylase deficient
What other than defective Phenylalanine hydroxylase can cause PKU?
Defective / deficient BH4 cofactor
What is the most common inborn error of metabolism?
Penylketonuria
What are the signs/symptoms of PKU?
- Musty smell in urine from phenylalanine metabolites
- CNS symptoms - retardatio, sizures, tremor
- Pale skin, fair hair, blue eyes
Why do those with PKU have pale skin, fair hair, blue eyes?
Lack of tyrosine conversion to melanin
How is pku mainly treated?
Dietary modifactions
- Phenylalanine restricted - synthetic aa mixtures use for food
- Phenylalanine level monitored
- No aspartame
- Need to consume tyrosine
Maternal PKU
Occurs in women w. PKU who consume phenylalanine
- High levels act as a teratogen
- Baby born w. microcephaly, congenital heart defects
When are babies screened for phenylalanine?
2-3 days after birth
- Maternal enzymes may normalise levels at birth
What are causes of defective BH4 (causes ~ 2% of PKU)
- Defective dihydropteridine reductase
- Also impaired BH4 synthesis
What other hormones are decreases in BH4 (deficiency other than phenylalanine)?
- Epinephrine, NE
- Serotonin
- Dopamine (thus increased prolactin)
How is BH4 deficiency treated?
- Dietary restriction of phenylalanine
- Supplementation of BH4
- L-dopa, carbidopa -> dopamine
- 5-hydroxytryptophan -> serotonin
What cofactor does tyrosine require?
BH4 (-> BH2)
What enzyme converts BH2 back to BH4?
Dihydropteridine Reductase
What molecule is used to convert BH2 back to BH4?
NADH (-> NAD+)
What enzyme does Metyrosine (a drug used for pheochromocytoma and hypertension) target?
Tyrosine Hydroxylase
- Tyrosine not converted to DOPA
What enzyme converts Tyrosine to Dihydroxyphenylalanine?
Tyrosine Hydroxylase
What enzyme converts DOPA to Dopamine?
DOPA decarboxylase (removes carboxylic acid)
What vitamin acts as a cofactor for DOPA decarboxylase?
B6
What inhibits DOPA decarboylase periphally ?
Carbidopa
What comination therpay can be used in patients in parkinsons?
Levodopa/carbidopa
- Levodopa is a dopamine precursor
- Carbidopa prevents peripherally conversion of L-DOPA to Dopamine - reducing side-effects
What enzyme converts Dopamine to NE?
Dopamine B-hydroxylase
What vitamin acts as a cofactor for Dopamine B-hydroxylase?
Vitamin C
What enzyme converts NE to Epinephrine?
Phenylethanolamine N-methyltransferase
- Adds methyl group
What acts as a cofactor for PNMT?
SAM (S-adenosyl Methionine)
- Donates methyl groups
What is SAM synthesised from?
ATP and methionine (aa)
What is the difference in structure between methionine and homocysteine (very similar structures)?
SAM (w/o methyl group and adenosine)
What molecules are created from SAM when it removes its methyl group in the conversion of NE to E?
- Adenosine
- Homocysteine
How is methionine regenrated?
Regenerated from homocysteine and N5-MethylTHF
- Makes Methionine (converted to SAM)
- and THF
What vitamins are required to make methionine and therefore SAM?
Folate (converted to N5-Methyl THF)
- B12 acts as a cofactor for homocysteine to be converted to methionine (and N5-Methyl THF -> THF)
What is added to tyrosine (along with other steos to make Thyroxine)?
Iodine
What cells make melanin?
Melanocytes
What enzyme converts Tyrosine to DOPA quinone (which is then converted into melanin)?
Tyrosinase
What are the 2 main types of oculocutaneous albinism? and what causes them?
- OCA Type 1 - Tyrosinase deficiency-
- OCA Type 2 - Tyrosine transporters
What are people with oculocutenous albinism at risk of?
- Sunburns, skin cancer
What is Chediak-Higashi Syndrome?
- Immunodeficiency
- OCA type II: Transporter defect - MTs dysfunctional`
What does ocular albinism result in?
Ocular albinism
What is Tyrosine broken down into?
Homogentistic acid (HGA)
Then:
- Fumarate and (glucogenic)
- Acetoacetate (ketogenic)
By HGA Oxidase
What enzyme breaks down HGA into Fumarate and Acetoacetate?
Homogentistic acid Oxidase
How is alkaptonuria inherited?
AR
What is alkaptonuria a deficiency of?
Homogentistic acid oxidase
What molecule builds up in alkaptonuria and what does this result in?
Increased Homogentistic acid
- Polymerisation -> dark pigment
- Pigment deposited in connective tissue (ochronosis)
What are the findings in alkaptonuria?
- Dark urine when left standing (due to polymerisation), discolouration in infancy
- Arthritis (large joints, knees, hips)
- Black pigment in cartilage, joints
- X-ray: calcification of intervertebral discs
- Other symptoms later in life
How is alkaptonuria diagnosed?
- Elevated HGA in urine/plasma
How is Alkaptonuria treated?
Dietary restriction
- Tyrosine an phenylalanine
What 2 enzymes break down catecholamines?
- Monoamine oxidase (MAO) Amine -> COOH
- Catechol-O-methyltransferase (COMT): Methyl to O2
What are epinephrine and NE broken down into?
Vanillylmadelic acid (VMA) - Excreted in urine
What is dopamine broken down into?
Homovanillic acid (HMA) - Excreted in urine
How can pheochromocytoma be diagnosed?
Metanephrin and normetanephrine in 24 hour urine collection
OR 24 hr collection of VMAs in urine
How does Selegline work in Parkinson’s?
MAO-b inhibitor
- Increase Dopamine
How does Entacapone and tolcapone work in Parkinson’s?
COMT inhibitors
- Increase dopamine
What are MAO inhibitors such as Tranylcypromine and Phenelzine used for clinically?
Depression (less used nowadays)
- Increase dopamine, NE and serotonin
What is Tyramine found in and what can Tyramine-rich foods cause in those on MAOi medications?
Cheese, red wine, some meats ‘cheese effect’
Similar to dopamine
- Sympathomimetic
- Hypertensive crisis
What amino acid is used to synthesise serotonin?
Tryptophan
What is Tryptophan converted to first before being converted to serotonin (5-HT)?
5-Hydroxytryptophan
What enzyme converts Tryptophan to 5-Hydroxytrptophan (precursor of serotonin)
Tryptophan Hydroxylase
- BH4 -> BH2
What is required as a cofactor for tryptophan hydroxylase?
BH4 (-> BH2)
What is carcinoid syndrome caused by?
GI tumours that secrete serotonin
Normally how much of tryptophan is converted to serotonin?
1%
how much of tryptophan is converted to serotonin in carcinoid syndrome?
Up to 70%
What molecule is depleted in carcinoid syndrome and what disease does this cause?
Tryptophan
- Pellagra
What are the effects of serotonin?
- Diarrhea (serotonin stimulates GI activity)
- Increased fibroblast growth and fibrogenesis -> valvular lesions
- Flushing (other mediators also)
What valves may be affected in patients with carcinoid syndrome? (due to increased serotonin)
Tricuspid and pulmonary
What enzyme breaks down serotnin into 5-Hydroxyindole acetaldehyde?
MAO
What is serotonin broken down into?
5-Hydroxyindole acetaldehyde (MAO)
-> 5-Hydroxyindoleacetic acid (5-HIAA)
What will be found in the urine in carcinoid syndrome?
5-HIAA
What are the symptoms of Pellagra?
- Hyperpigmented rash
- Exposed areas of the skin
- Red tongue (glossitis)
- Diarrhea and vomitting
- CNS: dementia, encephalopathy
- Dermatitis, diarhea and dementia
What vitamin deficiency can cause pellagra?
Niacin
What other than 5-HIAA can Serotonin be converted to?
Melatonin
What acts as a cofactor in the conversion of Tryptophan to Niacin?
B6
What is Niacin used to create?
NADH and NADPH
What is Hartnup disease?
AR
- Absence of transporter in PCT
- Loss of tryptophan in urine
- Symptoms of niacin deficiency
What is Histidine converted to Histamine by and what is a cofactor and what also is produced?
Histidine Decarboxylase
- Requires Decarboxylase
- CO2 produced in reaction
What is glycine (aa) required for?
Porphyrin ring - heme synthesis
What are the Carbons and nitrogens in heme from?
- Glycine
- Succinyl CoA
What is arginine used to create?
Creatinine (muscles)
Urea (urea cycle)
What amino acid and molecule does Nitric oxide synthase require?
Arginine and NADPH
To create Citrulline, Nitric oxide and NADP+
What is glutmate in the NS?
Excitatory NTs
What enzyme produces GABA from glutamate?
Glutamate Decarboxylase (B6 cofactor)
What are the branched chain amino acids (valine, leucine, isoleucine) broken down by (enzyme)?
a-ketoacid dehydrogenase
Where are branched chain amino acids (valine, leucine, isoleucine) broken down?
Muscle cells
What complex is a-ketoacid dehydrogenase a part of?
Branched-chain a-ketoacid dehydrogenase complex
What are the subunits in a-ketoacid dehydrogenase complex?
- E1: a-ketoacid dehydrogenase
- E2: dihydrolipoyl transacylase
- E3: dihydrolipoamide dehydrogenase
What are the cofactors for the a-ketoacid dehydrogenase complex?
- Thiamine
- Lipoic acid
What are the 3 steps of branched cahin amino acid metabolism?
- Transamination
- Decraboxylation
- Dehydrogenation
What is Valine broken down into?
Succinyl CoA (glucogenic)
What is Isoleucine broken down into?
Succinyl CoA (glucogenic) Acetyl CoA (ketogenic)
What is Leucine broken down into?
Acetyl-CoA
Acetoacetate
- Purely ketogenic aa
What is maple syrup urine disease due to a deficiency in?
A-ketoacid dehydrogenase
What will MSUD children have in their plasma?
- Increased branched chain AAs
- And alpha-ketoacids in plasma
What gives MSUD patients urine a sweet smell?
Alpha-ketoacid of isoleucine (all 3 branched AAs have alpha-ketoacids after transamination)
What is the main problem in MSUD?
Neurotoxicity due to build up of leucine
What will the clinical symptoms of MSUD be?
1st few days of life
- Lethargy, irratibility
- Apnea, seizures
- Cerebral oedema
How can MSUD be diagnosed>?
Elevated valine, leucine and isoleucine in plasma
What is the treatment of MSUD?
- Dietary restriction of branched-chain amino acids
- Monitoring AA concentrations
- Thiamine supplementation
How is Homocysteine made?
Methionine and ATP create:
- SAM
SAM has adenosine and Methyl group removed to create:
- Homocysteine
What is the enzyme that converts Homocysteine and Serine into Cystathionine?
Cystathionine Synthase (B6)
What is cystathionine metabolised into?
- a-ketobutyrate -> Succinyl-CoA
- Cysteine
What does cystathionine synthase require as a cofactor?
B6
What enzyme converts homocysteine back into Methionine?
Methionine synthase
What does Methionine synthase require as a cofactor?
B12
What is N5-methyl Tetrahydrogolate converted into by methionine synthase?
Tetrahydrofolate
What is a normal homocysteine level?
5-15 micromoles/L
What can cause mild-moderate elevations of homocysteine?
- B12/folate/B6 deficiecny
- May be linked to increased risk of CV disease
What is considered severe hyperhomocysteinemia?
> 100umoles / L
What are the common symptoms of Homocystenuria?
- Retardation
- Lens discolouration
- Long limbs, chest deformaties
- Osteoperosis in childhood
- Blood clots
- Early atherosclerosis (stroke, MI)
What is classic Homocystinuria due to?
Cystathionine B synthase (CBS) deficiency
How is homocystinuria treated?
- Avoid methionine
- Increased cysteine (now essential aa)
- B6 supplements
What are other causes of Homocystinuria / elevations outside of CBS deficiency?
- Methionine synthase deficiency
- Defective metabolism folate/B12 - MTHFR gene mutations
How are kidney stones in those with cystinuria prevented?
Methionine free diet
