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Metabolism > Nitrogen metabolism > Flashcards

Nitrogen metabolism Flashcards

1
Q

why is nitrogen essential for life

A
  • major constituent of RNA - needed for genetic continuity, development and survival
  • major constituent of protein - needed for biological structure and function
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2
Q

process of nitrgoen in body (basic)

A
  • dietary nitrogen
  • nitrogen metabolism
  • nitrogen excretion
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3
Q

nitrogen balance

A

dietary nitrogen intake = nitrogen excretion

in most adults

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4
Q

major source of dietary nitrogen

A

protein

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5
Q

reservoir pools

A

reservoir pool is needed for any balance input-output system to smooth the effects of high and low input stimulation
- unlike fat which have excess storage, protein stores are small and there is very little in the blood

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6
Q

positive nitrogen balance

A

= muscle / weight gain

  • anabolic states
  • growth in children
  • growth in pregnancy
  • growth in muscle builders
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7
Q

negative nitrogen balance

A

= muscle / weight loss

  • catabolic states
  • malnutrition
  • dieting
  • infection
  • cell toxicty
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8
Q

average adult daily protein intake

A

70g

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9
Q

average adult daily nitrogen intake

A

10g

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10
Q

how much nitrogen do we need to excrete per day

A

~10g because we ingest ~10g

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11
Q

main nitrgoen excretion product =

A

urea

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12
Q

how much urea is = to 10g nitrogen

A

22g urea/day needs to be synthesised and excretd to = 10g nitrgoen excretion

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13
Q

what is an excellent clinical measure of protein intake

A

the urea production/ excretion rate

it shows nitrogen balance

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14
Q

what does amino acid catabolism produce

A

urea, CO2 and H2O

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15
Q

digestion and absorption of dietary protein

A
  • dietary protein hydrolysed in gut to produce AA

- AA absorbed and released as necessary to maintain reservoir pool

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16
Q

what are amino acids

A
  • key building blocks of protein
  • essential for synthesis of glucose, hormones and rane of intermediary metabolites
  • major component of energy metaboism
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17
Q

structure of AA

A
  • carbon skeleton
  • amino group
               H
                |
H2N -----C-----COOH
                |
               H
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18
Q

Role of carbon skeleton of AA

A

Primary synthetic source of carbon. Catabolised to CO2 and H2O to produce energy

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19
Q

why is amino group of AA potentially toxic

A

potentially toxic

catabolism prodices highy toxic ammonium ions NH4+

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20
Q

toxic product of AA catabolism

A

NH4+ Ammonium ions

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21
Q

detoxification of ammonium ions, NH4+

A

conversion of NH4+ to urea - uses energy

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22
Q

why do we metabolise AA if potentially toxic?

A

value of the carbon skeletons in intermediary metabolite synthesis and energy production > energy cost of detoxification

AA are valuable - but not all equal

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23
Q

NEAA

A

non essesntial amino acids

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24
Q

why are some AA NEAA

A

the carbon skeleton of these AA can be synthesised as part of intermediary metabolism therefore they are not required in the diet

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25
Q

examples of NEAA

A
  • alanine
  • arginine*
  • asparagine
  • aspartate
  • cysteine
  • glutamate
  • glutamine
  • glycine
  • proline
  • serine
  • tyrosine
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26
Q

what is special about arginine

A

it is a NEAA but when things go wrong it becomes EAA

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27
Q

key NEAA and what they are synthesised from

A

alanaine from pyruvate
aspartate from oxaloacetate
glutamate from glutamine

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28
Q

what are EAA

A

AA that the carbon skeleton cannot be synthsised by the body, as part of intermediary metabolism

  • they are essential in the diet
  • mainly aromatic because cant synthesise benzine ring
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29
Q

what does a deficit of EAA result in

A

negative nitrogen balance because body must conserve EAA for protein synthesis and intermediary metabolism
- renal excretion of EAA is low and they are actively reabsored then reused and recycled

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30
Q

examples of EAA

A
  • histidine
  • isoleucine
  • leucine
  • lysine
  • methionine
  • phenylalanine
  • threonine
  • tryptophan
  • valine
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31
Q

what is special about histidine

A

it is only essential for growth, so sometimes classes as NEAA

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32
Q

process of making AA is called

A

transamination

- utilise c-skeleton of AA for synthesis and energy production, need to split the AA and detoxify the NH4+

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33
Q

what is transamination

A

transamination reactions are central to AA/nitrogen metabolism
- transfer of amino group of one AA to an 2-oxo acid, with formation of corresponding AA an 2-oxoacid

  • requires pyridoxal phosphate as cofactor
  • equilibrium reaction
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34
Q

cofact needed for transamination

A

pyridoxal phosphate = vitamin B6

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35
Q

transmationation reaction

A

R group from amino acid going to oxoacid 1 to from oxoacid 2

R group from oxoacid 1 goes to amino acid 1 to form amino acid 2

swapping of R group

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36
Q

enzyme for transamination

A

transaminase AKA aminotransferase

- specific for each AA, except threonine and lysine

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37
Q

transamination equilibrium

A
  • ensures supply of appropriate NEAA and EAA requird for proteinsynthesis
  • ensures the supply of appropriate c-skeletons for intermediary metabolism

e.g glutamate can replenish 2-oxoglutarate for the krebs cycle

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38
Q

glutamate and 2-oxoglutarate equilibrium

A
  • 2oxoglutarate is very abundant
  • therefore glutamate acts as main AA nitrogen pool via transamination
  • glutamate canbe used to maintain concentrations of other AA
  • when there are AA in excess, transaminatin with 2-oxoglutarate act as the 1st step of catabolism
  • BC glutamate can be deaminate
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39
Q

what is the only AA we can deaminate

A

glutamate can be deamintaed to ornithine AKA urea

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40
Q

example of glutamate being deaminated

A

if leucine is in excess, pass the AA of leucine group to oxoglutarate to make a different oxo-acid and glutamate.

glutama can then be deaminated to urea and the other oxoacid can be catabolised to H2O and CO2

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41
Q

B6

A

pyridoxine

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42
Q

inactive form of pyridoxial phosphate

A

pyridoxine = vitamin B6

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43
Q

active form of pyridoxine

A

pyridoxial phosphate = cofactor for transfamintion

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44
Q

Schiff Base formation

A
  • hydroxymethyl group of cofactor at postion 4 is oxidised to an aldehyde
  • aldehyde is essential for reaction between pyridoxial phosphate and primary amies

the condensation reaction betweem the aldehyde on the cofactor and the amino group of the AA = Schiff Base formation
= aldimine H-C=N

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45
Q

how is the pyridoxial phosphate achored in the active site of aminotransferase?

A

the highly negative charge of the phosphate on pyridoxial phosphate interacts with the postive chagre of thr arginine within the AS

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46
Q

what happens when pyrodixial phosphate is achored in transferase active site

A

the pyridoxamine phosphate is formed as an intermediate via schiff base formation, but remains locked in AS by arginine

  • AA and 2oxo acids with approrpiate AS specificity will equilibriate
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47
Q

role of arginine within the aminotransferase

A

immobilises the cofactor so transaminiation can occur

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48
Q

variations of schiff base formation

A 
common mechanism in AA metabolism
varies depending on architecture of the enzyme AS
- transamintiation
- deamination
- decarboxylation
- racemisation
- side chain radification
but always an equilibrium reaction
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49
Q

oxidative deamination

A
  • the first step in consigning the AA nitrogen to conversion to urea for excretion
  • irreversible reaction
50
Q

what is the first step in consigning the AA nitrogen to conversion to urea for excretion

A

oxidative deamination

51
Q

example of oxidative deamination

A

glutamate + H20 + NADP —> Oxoglutarate + NADPH + NH4+

enzyme: glutamate dehydrogenase
location: inner mitochondrial membrane of liver mitochondria

52
Q

most common AA dehydrogenase

A

glutamate dehydrogenase, represents 75% of nitrogen flux

53
Q

where is the glutamate dehydrogenase primarily located

A

inner mitochondrial memebrane of liver mitochondria

54
Q

what does oxidative deamination result in

A
  • liberation of NH4+ ions

- net loss of nitrogen from AA reservoir pool

55
Q

what must happen to ammonium ions released by glutamate dehydrogenase

A

they must be rapidly metabolised to urea cus they’re toxic

56
Q

carbamyl phosphate synthetase

A

enzyme in the liver mitochondria
- prepares ammonium ions to enter urea cycle:
catalyses the condensation of ammonium ions and bicarbonate ions to form carbonyl phosphate
- reqiuires 2 ATP

57
Q

UREA CYCLE

A
  1. condensation reaction to form carbamyl phosphate, using amino group from any AA that tansamiates to glutamate, which was then deaminated (1st input)
  2. carbamyl phosphate combines with ornithine to form citrulline
  3. aspartate doesnt have to be deaminated, and is the 2nd input of N to the urea cycle
  4. arginosuccinates forms from citrulline and aspartate, which then converts to fumarate (released) and arginine
  5. arginine is an NEAA, bc synthesised here
  6. complettion of cycle releases urea from arginine, to produce ornithine again
58
Q

1st input of nitrogen to urea cycle

A

condensation reaction to form carbamyl phosphate, using amino group from any AA that tansamiates to glutamate, which was then deaminated

59
Q

2nd input of nitrogen to urea cycle

A

aspartate doesnt have to be deaminated, and is the 2nd input of N to the urea cycle

60
Q

net reaction of urea cycle

A

CO2 + 3ATP + aspartate + 2H2O + NH4+

———>

urea + 2ADP + 2Pi + AMP + PPi + fumarate

61
Q

enzymes of urea cycle

A
  • carbamyl phosphate synthase
  • ornithine transcarbamylase
  • argininosuccinate synthetase
  • argininosuccinate lyase
  • arginase
62
Q

summary of urea cycle

A

2 amino acid nitrogens are detoxified at the expensie of 4 high energy bonds

63
Q

how does liver failure effect urea cycle

A

reduced abilty to synthesis urea results in hyperammonaemia and consequent morbidty and mortality

64
Q

what happens to urea from urea cycle

A

it is not further metabolised - it is excreted

  • urea is filtered by the kidneys
  • 40% is reabsored by passsive diffusion in renal tubules
  • renal excretion is not efficient
65
Q

neonatal symptoms from problems with nitrogen metabolism

A
  • children with severe urea cycle disorders wil show symptoms after 24 hours of life
  • irritable baby at first, followed by vomiting and increased lethargy
  • then seiures, hypotonia, respiratory alkalosis and coma may occur
  • sever sympotoms more common with OTC and CPS deficiency
  • can also occur with citrullinemia or ASA lyase deficiency
66
Q

ASA lyase

A

argininosuccinate lyase

67
Q

OTC

A

ornithine transcarbamylase

68
Q

CPS

A

carbamyl phosphate synthase

69
Q

What causes the neonatal symptoms from problems with nitrogen metabolism

A

rising ammonia levels in the blood

baby will die if untreated

70
Q

methods of adapting to live without a urea cycle

A
  • reduce nitrogen intake
  • reduce protein intake
  • increase nitrogen excretion
  • activate alternative pathways
  • minimise protein catabolism
  • maximise protein anabolism
71
Q

Why must problems of urea cycle be detected early

A

will effect CNS leading to mental retardation

72
Q

role of the diet in reducing need for urea cycle

A
  • restriction of NEAA
  • supplementation of EAA
  • supplementation of EKA
73
Q

role of pharmacology in reducing the need for urea cycle

A

sodium benzoate
sodium phenylacetate
sodim phenylbutyrate

74
Q

OTC deficiency: clinical and biochemical symptoms

A

clinical:
- failure to excrete nitrogen
- encephalopathy
- coma
- death

Biochemical:

  • hyperammonaemia
  • arginine becomes EAA
75
Q

treatmetn of OTC deficiency

A
  • reduce protein intake
  • supplement EAA
  • using transamination
  • supplement EOA
76
Q

how is argininge deficiency treated in OTC deficiency

A

dont need to directly supplement arginine

- supplement citrulline which means bypass OTC part of urea cycle, and rest can occur as normal to produce arginine

77
Q

why does supplementation of EOA help OTC deficiecny

A

it activates alternative nitrogen excretion pathway

78
Q

what EOA can be supplemented to help OTC deficiency

A
  • sodium benzoate

- sodium phenylbutyrate

79
Q

example of supplementing EOA to help OTC deficiency:: sodium benzoate

A
  • sodium benzoate is activated by coenzyme A
  • conjugates with glycine in the liver and kidney
    = hippuric acid
  • hippuric acid is efficinetly excreted by the kidney
    = 1 amino nitrogen removed
80
Q

example of supplementing EOA to help OTC deficiency:: sodium phenylbutyrate

A
  • sodium phenylbutyrate activated by Coenzyme A
  • metabolised to phenylacetate which conjuagtes with gluatine in liver and kidney
    = phenylacetylglutamine
  • efficiently excreted by the kidney
    = 2 amino nitrogens removed
81
Q

how are hippuric acid and phylyacetylglutamine excreted by the kidnyes

A

efficiently byt filtration and tubular secretion

82
Q

which EOA removes 2 amino nitrogens

A

sodium phenylbutyrate by excretion of phenylacetlyglutamine

83
Q

which EOA removes 1 amino nitrogen

A

sodium benzoate by excretion of hippuric acid

84
Q

ASA synthase deficiency: clinical and biochemical symptoms

A

same as OTC deficiency

clinical:
- failure to excrete nitrogen
- encephalopathy
- coma
- death

Biochemical:

  • hyperammonaemia
  • arginine becomes EAA
85
Q

treatment of ASA synthase deficiency

A

supplement with arginine

86
Q

can you supplement ASA synthase deficiency with citrulline

A

no, becuase the problem in the urea cycle is downstream of citrulline and so it would have no therapuetic effect

87
Q

ASA lyase deficiency: clinical and biochemical symptoms

A

same as OTC deficiency if acute

clinical:
- failure to excrete nitrogen
- encephalopathy
- coma
- death

Biochemical:

  • hyperammonaemia
  • arginine becomes EAA

chronic ASA lyase deficiency causes much less severe symptoms
- friable hair from arginine deficiency is more obvious than hyperammonaemia

88
Q

why is chronic ASA lyase deficiency less severe than acute ASA lyase deficiency

A

ASA is actively secreted by the kidney which removes 2XN

excretion of ASA is more efficient that urea secretion!

89
Q

treatment of ASA lysase deficiency

A
  • supplement with arginine

- activate alternative pathways ONLY during rare acute decompensation episodes

90
Q

how is it possible to live without properly functioning urea cycle

A
  • reduce protein intake
  • activate alternative exretion pathways
  • supplement with argining or citrulline
91
Q

metabolism of phenylalanine

A

EAA that is primarily metabolsied to tyrosine

92
Q

Phenylalanine hydroxylase deficiency causes

A

phenylketonuria (PKU)

93
Q

what is phenylketonuria

A

Phenylalanine hydroxylase deficiency

  • autosomal recessive disorder
  • incidence 1:10,000
  • heterozygous 1:50

[phenylalanine] increases
[phenylalanine metabolite] increases
but cannot be metabolised and so tyrosine becomes an EAA

94
Q

clinical presentation of Phenylalanine hydroxylase deficiency

A

severe mental retardatio

95
Q

pathogenesis of Phenylalanine hydroxylase deficiency

A

increased phenylalanine inhibits tyrosine metabolism which reinforces the tyrosine deficiency

96
Q

why is tyrosine deficieny a problem

A

tyrosine is used to produce L-DOPA which is esentail in first two yar of life for neurodevelopment
- untreated = irreversible severe mental retardation, IQ<50

97
Q

Treatment of Phenylalanine hydroxylase deficiency

A

needs early diagnosis - newborn dried blood spot screening

  • normalise [phenylalanie] by restriction it inthe diet and supplementing EAA and vitamins.
  • diet for life that is started from bith and continued forever
  • non compliance in teens shown to increase [phenylalanine] which reduces pigmentation of hair and eyes
  • pigmentation returns when they follow their diet again
98
Q

pruine nucleotides

A

adenine (A)
guanine (G)

  • in DNA and RNA
99
Q

pyrimidine nucleotides

A

cyctosine (C) in DNA and RNA
thyrosine (T) in DNA
uracil (U) in RNA

100
Q

nitrokgen intake from nucleotides

A
  • signicicantly less than from protein
  • v poor dataon dietary intake of nucleotides
  • very low in vegans
  • represents ~27% of dietary nitrogen intake
  • end product of metabolism for excretion is uric acid
  • uric acid is relatively insoluble
101
Q

sources of nucleotides

A

some from diet, poor data

or synthesised engdogenously - very thermodynamially costly!!!

102
Q

endogenous synthesis of purines

A

glutamine glycine and asparate via inosine

103
Q

endogenous synthesis of pyrimidines

A

AA via carybamyl phosphate, synthesised in cytosol

104
Q

nucleotide metabolism

A

very little is metabolsied, it is mostly dietary nitrogen

105
Q

end product of purine metabolism

A

insouble uric acid, via hypoxanthine/xanthine

106
Q

end product of pyrimidine metabolism

A

soluble beta-ureidopropionic acid

107
Q

what happens to most neucleotides when metabolsied

A

they are salvaged, becuase they are energetically expensive to make so they ae recycled instead

108
Q

enzyme for salvage of purines

A

HGPRT

109
Q

enzyme for salvage of pyrimidines

A

UTPRT

110
Q

primary clincal problem with purine metabolism

A

gout

111
Q

what is gout

A

uric acid precipitation

112
Q

causes of gout

A

increased dietary purines
increased purine synthesis
= reduced HGPRT activity

113
Q

treatment of gout

A

reduce high nucleotide foods

allopurinol; inhibts conversion of hypoxanthine to uric acid

114
Q

What is no HGPRT activity a sign of

A

Lesch-Nyhan Syndrom

caused by mutations in the HGPRT gene

115
Q

what is the role of HGPRT1

A

enzyme responsible for purine recycling to ensure all cells have plentiful supply of building blocks for RNA and DNA

116
Q

what does HGPR1 mutations causes

A

deficiency of abscence = purines broken down but not recycled causes abnormally high levels of uric acid

117
Q

what else is deficiency of HGPR1 associated with

A

abnormally low dopamine in the brain

causes movement problems and behavioural problems

118
Q

Acute intermittent porphyria (AIP) is caused by a deficiency in which enzyme

A

porphobilinogen deaminase

119
Q

Which vitamin is the source of the prosthetic group of the aminotransferases (transaminases)

A

pyridoxine (vitamin B6)

120
Q

what is NOT an important intermediate in the excretion of urea

A

uric acid

Metabolism (11 decks)

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