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biochem - protein metabolism Flashcards

1
Q

primary site of amino acid metabolism

A

LIVER

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2
Q

what happens to components of amino acid

A
  • amino groups -> excreted as urea
  • carbon skeletons -> metabolic fates (acetyl coa, pyruvate, krebs cycle intermediates
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3
Q

what is cystinuria

A
  • failure in reabsorption and uptake of cystine, ornithine, arginine, lysine (COAL)
  • cause cystine kidney stones
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4
Q

what is hartnup’s disease (neuropsychiatric symptoms)

A
  • failure in the reabsorption and uptake of trp, phe and other neutral amino acids
  • cerebellar ataxia (lack of coordination of involuntary
    movement)
  • pellagra-like symptoms eg. skin lesions, dermatitis (nicotinic acid/nicotinamide deficiency)
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5
Q

what is nitrogen balance

A
  • intake of N = output of N

+ve N balance:
- intake of N > output of N (eg growth, pregnancy)

-ve N balance
- intake of N < output of N

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6
Q

amino acid with the highest concentration in blood

A
  • glutamine
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7
Q

what happens to excess amino acids

A
  • deamination (removal of N group) to form KETOACIDS

via:
- oxidative deamination **(most common)
- transamination
- non-oxidative deamination

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8
Q

why is L-glutamate dehydrogenase (enzyme in oxidative deamination) so special

A
  • can utilise both NAD+ and NADP+ as oxidizing agents (forms NADH, NADPH) -> used in energy pdn (NADH) or biomolecule synthesis (NADPH)
  • reaction is reversible
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9
Q

what is transamination

A
  • conversion of an amino acid to ketoacid, while another ketoacid accepts the amino group to form an amino acid
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10
Q

what is required for PLP (pyridoxal phosphate) cofactor synthesis

A
  • Vit B6
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11
Q

what is the purpose of transamination

A
  • (transdeamination) releasing ammonia in the form of NH4+ from OTHER amino acids (other than glutamate) through transamination with glutamate -> then oxidative deamination of glutamate
  • synthesis of non-essential amino acids (through conversion between diff types of amino acids)
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12
Q

what is an indication of necrosis in muscles/ liver/ brain

A
  • raised blood serum ALT, AST

ALT - alanine aminotransferase (used in alanine-glutamate transamination)
AST - asparatate aminotransferase (used in aspartate-glutamate transamination)

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13
Q

structure of an aminotransferase

A
  • PLP bonded to enzyme (usually an amino acid, eg Lys)
  • bond is known as a SCHIFF BASE/ aldimine linkage
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14
Q

mechanism of PLP dependent transamination

A
  1. transamination
  2. tautomerization
  3. hydrolysis
    *forms ketoacid from amino acid

steps are repeated but in reverse for 4. 5. 6.
*forms amino acid from ketoacid

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15
Q

describe the phenomenon of ion trapping (NH4+)

A
  • pertains to NH4+
  • under physiological pH of 7.4 (pKa NH4+ = 9) -> majority of NH3 exists as NH4+ (associated form) -> cannot exit cell membrane and cannot be excreted
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16
Q

how is ion trapping overcome

A

glutamine can be transported out of cell (glutamine = glutamate + NH4+ = a-KG + 2NH4+)

  • NH4+ converted to glutamate (involves glutamate dehydrogenase, a-KG, NADPH)
  • glutamate converted to glutamine (involves glutamine synthetase) -> transported out of cell to kidney
  • glutamine converted back to glutamate to release NH4+ outside of cell (involves glutaminase) -> excreted
  • glutamate converted back to aKG to release NH4+ (involves glutamate dehydrogenase) -> excreted

**one glutamine releases 2 NH4+ molecules

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17
Q

why is ammonia toxic to humans

A
  • presence of glutamate dehydrogenase -> high NH3 concentration forces backward reaction (conversion of aKG -> L-glutamate)
  • backward reaction depletes NADH/ NADPH -> inability to generate energy -> TOXICITY
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18
Q

regulation of urea cycle (4)

A
  1. compartmentalization (mitchondria vs cytosol)
  2. transcriptional & translational control of enzymes
  3. feed forward activation (activation by reactants)
  4. allosteric regulation
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19
Q

what is the rate limiting enzyme in urea cycle

A
  • CP synthetase 1 (CPS1)
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20
Q

what is CPS1 allosterically activated by

A

N-acetylglutamate

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21
Q

how is N-acetylglutamate activated

A
  • formed from glutamate via addition of arginine -> high [Arg] -> increased activation of N-acetylglutamate -> activation of CPS1
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22
Q

why is urea excreted instead of ammonia

A
  • urea is more soluble -> less water wasted to excreted same amount of water
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23
Q

enzyme defect in urea cycle - inherited disease

A
  • Carbamoyl phosphate synthetase I -> Hyperammonemia Type I
  • Ornithine transcarbamoylase -> Hyperammonemia Type II
  • Argininosuccinate synthetase -> Citrullinemia
  • Argininosuccinate lyase
    (Argininosuccinase) -> Argininosuccinic aciduria
    (Argininosuccinic acidemia)
  • Arginase -> Argininemia

*any urea enzyme defect causes HYPERAMMONEMIA

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24
Q

effect of hyperammonemia

A

hepatic coma, nausea, seizures, ataxia

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25
Q

how to treat hyperammonemia

A

give glucose and arginine
- arginine -> required for urea formation from NH4+ -> reduce blood [NH4+]
- glucose -> metabolism of glucose provides reducing equivalents → allow GDH to remove ammonia + glucose is metabolized to aspartate → feeds into urea cycle for activation

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26
Q

fate of NH3

A
  1. Assimilation (Incorporation into organic compounds)
    a) by glutamine synthetase
    b) by glutamate dehydrogenase
    c) by carbamoyl phosphate synthetase
  2. Excretion
    a) as ammonium ions
    b) as urea
    c) as creatinine
    d) as uric acid
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27
Q

ketogenic vs glucogenic amino acids

A

ketogenic: aa has potential to form ketone bodies under starvation

glucogenic: aa has potential to form glucose under starvation

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28
Q

what fuel does brain use

A
  1. glucose
  2. ketone body (if no glucose)
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29
Q

why are ketogenic aa not considered glucogenic even though they enter TCA and can eventually form glucose

A
  • enters TCA as acetyl-coA (2C) -> 2 decarboxylation steps of TCA removes the acetyl-coA C -> C from aa is lost -> not counted as glucogenic
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30
Q

aa that are both ketogenic and glucogenic

A

phenylalanine, tryptophan, leucine, isoleucine, valine

*can form both acetoacetate (ketone body) and TCA metabolites

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31
Q

what happens in leucine/ isoleucine turnover disorders (ie metabolism disorder)

A
  • maple syrup urine disease -> DARKENING of urine
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32
Q

how is NH3 in muscles primarily removed (2)

A
  • glucose-alanine cycle (using alanine as carrier of NH3) -> closed cycle between liver and muscle
  • through amination of aKG to glutamine -> transport to liver (less common, alanine preferred)
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33
Q

how is NH3 in muscles produced (2)

A
  • breakdown of amino acids
  • substrate level phosphorylation (from ADP)
34
Q

how does substrate level phosphorylation produce NH3

A
  • 2 ADP used to generate ATP and AMP (consequence of generating energy)
  • AMP needs to be deaminated to form IMP
35
Q

essential vs non essential amino acids

A

essential
- needed in the diet to ensure positive nitrogen balance
- body CANNOT synthesize from simple precursors
- body CANNOT synthesize enough for its own bodily
needs

non-essetial
- not needed in diet
- body CAN synthesize from precursor
- body CAN synthesize enough for own needs

36
Q

glutamate metabolisms that can occur (4)

A
  1. synthesis of non essential aa (aspartate, alanine, glutamine, ornithine, proline)
  2. synthesis of aKG
  3. synthesis of glutathione
  4. synthesis of GABA
37
Q

glutamine metabolisms that can occur (4)

A
  1. synthesis from glutamate + catabolism to glutamate
  2. transamidation
  3. synthesis of purines/ pyrimidines
  4. nucleotide metabolism (forming CTP and GMP)
38
Q

metabolism of aspartate & asparagine

A
  1. synthesis of aspartate from oxaloacetate (by transamination)
  2. synthesis of asparagine from aspartate
  3. synthesis of aspartate from asparagine
  4. synthesis of purines/ pyrimidines from aspartate
39
Q

how is tyrosine formed from phenylalanine

A
  • phenylalanine hydroyxylase + cofactor tetrahydrobiopterin
40
Q

how is tetrahydrobiopterin regnerated

A
  • by enzyme dihydropteridine reductase, with one NADPH molecule
41
Q

phenylketonuria pathogenesis and presentation

A
  • deficiency of enzyme in phenylalanine metabolism -> cause metabolic block and phenylalanine is shunted to other pathways

presentation
- high amounts of PHENYLPYRUVATE, phenyllactate & phenylacetate in urine (normal: trace amounts)
- symptoms of mental retardation due to phenylpyruvate buildup

42
Q

enzyme defects in phenylketonuria (3)

A
  • phenylalanine hydroxylase (classical)
  • dihydropteridine reductase OR biopterin synthesis (non-classical, related to terahydrobiopterin generation)
43
Q

enzyme defect in tyrosinemia type 1 (1)

A
  • fumarylacetoacetate hydrolase
44
Q

how to treat phenylketonuria in newborns

A
  • supply tyrosine and reduce phenylalanine from diet
    OR
  • introduce smart living microbes into GI -> convert excess phenylalanine to tyrosine
45
Q

what enzyme defect causes albinism

A
  • tyrosinase (Cu-dependent Tyr hydroxylase) -> prevents formation of melanin from tyrosine
46
Q

treatment of parkinson’s disease

A
  • administer DOPA (needed by CNS cells to transmit info via dopamine)
  • administer DOPA analogs (cannot cross BBB; carbidopa, methyldopahydrazine) -> inhibits dopamine carboxylase around the body except brain -> reduce systemic side effects of dopamine administration
47
Q

how to synthesize a primary amine from an amino acid

A
  • decarboxylation using an enzyme decarboxylase
48
Q

types of physiologically important amines and their synthesis routes

A
  • histamine (from histidine)
  • GABA (from glutamate)
  • serotonin (from 5-hydroxytryptophan)
  • dopamine (from DOPA)
  • tyramine (from tyrosine)
49
Q

what are some examples of polyamines

A
  • putrescine, spermidine, spermine
50
Q

functions of polyamines

A
  • polycationic -> can interact with nucleic acids (polyanions) by binding to phosphate groups -> DNA stabilization & packaging
  • cell growth and proliferation
51
Q

is methionine needed for polyamines synthesis

A

yes. need methionine to form S-adenosylmethionine

52
Q

how does creatine act as a storage of energy

A
  • creatine can be converted to creatine phosphate by creatine kinase in muscles
  • energy needs: creatine kinase can dephosphorylate creatine phosphate anytime to produce ATP

*most abundant source of ATP in muscles is creatine phosphate

53
Q

what happens to creatine phosphate that is stored and not used

A
  • broken up over time -> to form creatinine which is excreted
54
Q

nitrogen substances excreted by body

A
  • urea: 30g
  • creatinine: 1-1.8g
  • NH4+: 0.7g
  • uric acid: 0.5-1g
55
Q

components of a nucleotide (3)

A
  • inorganic phosphate (Pi or HPO32-)
  • 5-carbon sugar (D-ribose or 2-deoxy-D-ribose)
  • nitrogenous base (purine or pyrimidine)
56
Q

how does caffeine keep us awake

A
  • caffeine are purine derivatives
  • binds and inhibits phosphodiesterase -> prevents breakdown of cyclic AMP -> cyclic AMP keeps us awake
57
Q

what are the components of nucleosides (2)

A
  • nitrogenous base (purine/ pyrimidine)
  • sugar ring

*diff btwn nucleoside & nucleotide is phosphate group
*nucleosides are more soluble than its free nucleotide

58
Q

two important nucleotides to know

A
  • SAM (S-adenosylmethionine) -> METHYL donor
  • PAPS (3’-phosphoadenosine 5’-phosphosulphate) -> SULFUR donor
59
Q

steps in the biosynthesis of purine nucleotides

A
  1. converting ribose-5-phosphate to PRPP (ATP dependent)
  2. de novo pathway
  3. formation of AMP and GMP from IMP
  4. formation of purine ribonucleoside triphosphate
60
Q

how is the conversion of ribose-5-phosphate to PRPP regulated

A
  • regulation of PRPP synthetase (activated by Pi, inhibited by purine ribonucleotides)
61
Q

what is the de novo pathway in purine nucleotide synthesis

A
  • pathway that converts PRPP to IMP
62
Q

how is the de novo pathway in purine nucleotide synthesis regulated

A
  • glutamine-PRPP amidotransferase upregulated by PRPP, inhibited by AMP, GMP
63
Q

how is the synthesis of AMP/ GMP from IMP regulated

A
  • end product inhibition
64
Q

function of purine salvage pathways

A
  • recover catabolised free nitrogenous bases and incorporate them into purine synthesis by binding to PRPP
65
Q

bases involved in purine salvage pathways

A

catalysed by HGPRT
- hypoxanthine + PRPP -> IMP
- guanine + PRPP -> GMP

catalysed by APRT
- adenine + PRPP-> AMP

66
Q

how is pyrimidine nucleotide synthesis regulated

A
  • CPS II inhibited by end product UTP
  • OMPDC (orotidine 5-monophosphate decarboxylase) inhibited by end product UMP
67
Q

bases involved in pyrimidine salvage reactions

A

catalysed by ribose 1-phosphate
- uracil, cytosine -> uridine, cytidine

catalysed by deoxyribose 1-phosphate
- thymine -> thymidine

68
Q

in biosynthesis of deoxyribonucleotides from ribonucleotides, when does reduction occur

A
  • at NUCLEOTIDE level; ie ribonucleotide -> deoxyribonucleotide (NOT sugar level; ie ribose -x-> deoxyribose)
  • nucleotide is at the DIPHOSPHATE level (ie NDP -> dNDP)

*reaction is mediated by ribonucleotide reductase

69
Q

conditions required for proper functioning of ribonucleotide reductase (3)

A
  • Fe-dependent
  • requires NADPH as the reducing agent
  • contains thioredoxin as mediator protein (NADPH reduces thioredoxin reductase -> reduce thioredoxin -> reduce ribonucleotide reductase -> reduce NDP)
70
Q

what are the 3 main sites of ribonucleotide reductase

A
  • catalytic site -> site of NDP catalysis to dNDP
  • activity site -> site where ribonucleotide reductase can be activated/ inactivated; determined by ATP/ dATP
  • specificity site -> determines type of NDP that will be reduced at catalytic site (diff NDPs exist -> ADP, CDP, UDP, GDP)
71
Q

purpose of 1:1:1:1 ratio of deoxyribonucleotide pdn by ribonucleotide reductase

A
  • equal amount of each building block -> prevents mutations
72
Q

what is the FINAL END PRODUCT of all purine catabolism (AMP, IMP, XMP, GMP)

A
  • URIC ACID
73
Q

what is the FINAL END PRODUCT of all pyrimidine catabolism (CMP, UMP)

A
  • malonyl-CoA

*can be fed back into metabolic pathways like lipid synthesis -> NOT AN EXCRETORY PRODUCT

74
Q

diseases related to purine metabolism (4)

A
  • lesch-nyhan syndrome
  • gout
  • von Gierke’s glycogen storage disease
  • SCID
75
Q

Lesch-Nyhan syndrome pathogenesis

A
  • sex linked congenital; more common in MALES
  • severe HGPRT deficiency -> accumulation of PRPP -> excess de novo pathway activation -> increase purine nucleotide synthesis & breakdown -> increase URIC ACID

presentation:
- neurological abnormality

76
Q

what is gout

A
  • disease characterized by painful arthritic joint inflammation (acute arthritis) due to urea crystal precipitation (can also ppt in kidneys as stones)
  • caused by high uric levels in blood

pathogenesis
- impaired uric acid excretion
- excessive uric acid production (1. HGPRT deficiency in Lesch-Nyhan syndrome; 2. glucose-6-phosphatase deficiency in von Gierke’s glycogen storage disease causing G6P increase -> ribose-5-P increase -> PRPP increase)
- overactivity of PRPP synthetase

77
Q

treatment of gout

A
  • colchicine -> anti-inflammatory
    OR
  • allopurinol -> hypoxanthine analogue & inhibitor of xanthine oxidase + inhibits PRPP amidotransferase activity
78
Q

what is SCID (severe combined immunodeficiency disease)

A
  • inherited disorder, fatal in infancy due to lack of immune response to infection
  • T and B lymphocytes cannot proliferate
  • 30% SCID patients associated with adenosine deaminase (ADA) deficiency
79
Q

SCID pathogenesis

A
  • ADA involved in deamination of adenosine & deoxyadenosine -> ADA deficiency causes metabolic block -> increase adenosine & deoxyadenosine -> diverted to form more dATP
  • dATP accumulation inhibits NDP reductase at activity site -> prevent synthesis of dNTPs -> T & B cells cannot proliferate
80
Q

diseases related to pyrimidine metabolism

A
  • orotic aciduria
81
Q

orotic aciduria pathogenesis and presentation

A
  • inherited disorder

type 1 orotic aciduria
- deficiency in OPRT & OMP decarboxylase
- excretion of large amounts of orotic acid in urine

type 2 orotic aciduria
- deficiency in OMP decarboxylase

presentation
- retarded growth, severe anemia

82
Q

how to treat orotic aciduria

A
  • supply uridine or cytidine
  • use salvage enzyme to bypass pyrimidine de novo pathway

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