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Biochemistry II > Amino metabolism - AA I > Flashcards

Amino metabolism - AA I Flashcards

1
Q

Draw the structure of glutamine, glutmatate and α-ketoglutarate.

A
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2
Q

Briefly describe the general pathway of ingested N.

A

food proteins ingested,
then reach intestinal lumen: are cleaved

  1. by proteases to peptides
  2. by peptidases to amino acids
  3. by bacteria to NH3

​⇒ absorbed by liver

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3
Q

In which forms is N excreted from the body?

A
  • urea
  • NH4+
  • also: creatine, urate
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4
Q

When can nitrogen balance be considered positive, or negative?

Examples for each.

A
  • negative: excreted amount of N > ingested amount of N
    → starvation, diseases, senescence
  • positive: Nin > Nex
    → children, pregnancy, refeeding
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5
Q

What are the 2 functions of proteases?

In which form are they produced?

A
  • digestion of exogenous proteins (food)
  • degradation of endogenous proteins (protein turnover)

BUT: produced as zymogens
→ need proteolitic activation

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6
Q

What are endopeptidases?

Examples.

A

break peptide bonds of nonterminal amino acids (i.e. within the molecule)

  • pepsin, enteropeptidase
  • Ser proteases (trypsin, chymotrypsin, elastase)
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7
Q

What are exopeptidases?

Classify.

A

peptidase that catalyzes the cleavage of the terminal peptide bond

  • carboxypeptidases
  • aminopeptidases
  • di-, tripeptidases
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8
Q

Which enzymes facilitate protein turnover intra- and extracellularly?

A
  • extracellular: collagenases, metalloproteases, ellastases
  • intracellular: cathepsins (in lysosomes), ubiquination
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9
Q

What is the fate of the amino group?

A

it is either

  • transaminated → used for biosynthesis of AAs
  • deaminated → NH4+ formed
  • incorporated in form of NH3 into organic compounds (e.g. for excretion via urine)
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10
Q

What is a transamination reaction?

Which group of enzymes catalyzes it?

A

catalyzed by transaminases

reversible exchange of an amino- and an oxo-group
→ 2 pairs required, 1 always: α-KG + glu

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11
Q

What are 2 of the most important transaminases?

Which reactions are catalyzed by them?

A

ALAT = Ala aminotransferase
(clinically: GPT = glu-pyruvate transaminase)

α-KG + Ala → Glu + pyruvate

ASAT = Asp aminotransferase
(clinically: GOT = glu-OXA transaminase)

α-KG + Asp → Glu + OXA

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12
Q

What is the clinical relevance of ALAT and ASAT?

A

non-functional plasma enzymes
= markes of tissue damage

  • ALAT = liver (in cytosol)
  • ASAT = heart/muscle (in mito.)

→ De Ritis ratio:

  • ASAT/ALAT < 1 → minor liver damage
  • ASAT/ALAT > 2 → severe mit. damage, myocardial infarcts, severe muscle damage
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13
Q

What is the prostethic group of transaminases?
General function?

It is a derivate of which vitamin?

Structure(s).

A

pyridoxal-P = der. of vit B6
bound to a Lys residue of enzyme as a Schiff base

⇒ transfers amino-group from AA to ketoacid
pyridoxal-P (PLP) → pyridoxamine-P (PMP)

Schiff base = aldehyde, but N instead of O

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14
Q

In which enzymes can PLP be found as the prostethic group?

A
  • transaminases
  • amino decarboxylases
  • D/L amino racemases
  • Ser-hydroxymethyltransferase
  • Ser-Thr dehydratase
  • cystathione synthase
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15
Q

Describe the mechanism of transamination.

A
  1. PLP + amino-group → aldimine + H2O
  2. forming further Schiff base tautomers
  3. C-N double bound is cleaved → ketimine
  4. ketimine + H20 → α-ketoacid + pyridoxalamine-P
  • *​**then reverse reaction, amino-group transferred
  • *to α-KG to form glu**, PLP reformed
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16
Q

What is deamination?

List the 5 types.
Which one is the most important one?

A

amino group of AA is released as NH4+​

  • oxidative deamination: loss of α-amino group (via GLDH)e
  • O2 dep. ox. deamination: loss of α-amino group w/ flavoproteins
  • eliminating deamination: loss of α-amino group during catabolism
  • hydrolytic deamination: loss of β-, μ-amino group
  • deamination via nucleotide metabolism
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17
Q

Which enzyme catalyzes oxidative deamination?

Where is this enzyme located in the cell?

Reaction + structures.

A

glutamate dehydrogenase = GLDH
mitochondrial enzyme, conversion of Glu to α-KG

Glu + NAD+ + H2O → α-KG + NADH/H+ + NH4+

or: reverse reaction can be used to incorporate free ammonium into org. compounds

via formation of intermediate, not relevant though

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18
Q

How is GLDH regulated?

Therefore, what is its main function?

A

regulated allosterically by

  • ATP/GTP → inhibited, act. reverse reaction
  • (cf. own card)*
  • ADP/GDP → activated

⇒ dependent on energy status of cell, main function is to provide substrates for citrate cycle (α-KG, NADH/H+) rather than fixation of NH4+

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19
Q

Where can the 2 isoenzymes of GLDH be found?

A

glutamate dehydrogenase

  • GLUD 1: in liver, kidney, other tissues
  • GLUD 2: in brain, testis
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20
Q

Which enzymes catalyze hydrolytic deamination?

What is it?

Reactions.

A

AA hydrolyzed to release NH4+

  • glutaminase: Gln + H2O → Glu + NH4+
  • asparaginase: Asn + H2O → Asp + NH4+
21
Q

Which enzyme is responsible for eliminating deamination?

Reaction.

A

Ser-Thr dehydratase
uses PLP as prosthetic group

catalyzes deamination in 2 steps:

  1. Ser/Thr + PLP → H2O + aminoacrylate
  2. aminoacrylate + H2O → PLP + pyruvate (Ser)/α-ketobutyrate (Thr)
22
Q

Which enzymes catalyze O2 dependent oxidative deamination reactions?

Differentiate.

A

AA oxidases
use O2 to deaminate AA to α-ketoacids via electrontransfer to flavoproteins, stereospecific

  • D-AA oxidases: in peroxisomes, use FAD
    → prod. H2O2 used for detoxification
  • L-AA oxidases: in ER, use FMN
    → less important bc L-AA not physiological
23
Q

What is transdeamination?

Function.

A

process where a transamination is linked to a second reaction which results in deamination

→ action of transaminase, then GLDH

  • glucose/energy provided via α-ketoacid
  • energy provided via NADH
  • NH4+ excreted
24
Q

What is the function of the urea cycle?

Where does it happen?

Which enzymes catalyze which step?

A

ONLY in LIVER

production of urea from ammonia that was incorporated into Gln, Ala
→ excreted via urine

  1. carbamoyl phosphate synthetase I
  2. ornithine transcarbamoylase
  3. arginosuccinate synthetase
  4. arginosuccinate lyase
  5. arginase

(to minor extent in kidney)

25
Q

Which enzyme catalyzes the first step of the urea cycle?

Reaction + structures.

Where does the reaction take place?

A

carbamoyl phosphate synthetase I (CPT I)
in mitochondrial matrix

bicarbonate + ammonium form carbamoyl-P,
2 ATPs used

carbamoyl contains first of 2 NH2 groups of urea

26
Q

Which enzyme catalyzes the second step of the urea cycle?

Reaction + structures.

Where does the reaction take place?

A

ornithine transcarbamoylase
in mitochondrial matrix

carbamoyl group transferred to ornitihine,
citrulline formed

27
Q

What must happen with ornithine before it can be further processed in the urea cycle?

Explain.

A

since first 2 steps located in mitochondrial matrix, but step 3-5 in cytosol

→ ORNT1 antiporter in inner mit. membrane imports citrulline, exports ornithine to cytosol

28
Q

Which enzyme catalyzes the third step of the urea cycle?

Reaction + structures.

Where does the reaction take place?

A

arginosuccinate synthetase
in cytosol

condensation of citrulline + Asp, form arginosuccinate, ATP → AMP (2 ATP equivalents)

second of 2 NH2 groups of urea provided by Asp

29
Q

Which enzyme catalyzes the fourth step of the urea cycle?

Reaction + structures.

Where does the reaction take place?

A

arginosuccinate lyase
in cytosol

arginosuccinate cleaved to fumarate + Arg

30
Q

Which enzyme catalyzes the fifth step of the urea cycle?

Reaction + structures.

Where does the reaction take place?

A

arginase
in cytosol

arginine hydrolyzed to urea and ornithine

(ornithine then transported via ORNT1 into mitochondria)

31
Q

How much ATP is needed for the synthesis of urea?

In which reactions?

A

4 ATP equivalents

  • 2 ATP for CPT I
  • 2 ATP equ. (ATP → AMP) for arginosuccinate synthetase
32
Q

What is the function of N-acetyl Glu?

How is it produced?

A

necessary to activate CPS I
= rate limiting step of urea cycle

produced from Nac-Glu synthase
acetyl-CoA + Glu → N-acetyl Glu

33
Q

Which substances regulate the activity of Nac-Glu synthase?

Consequence?

A

arginine

→ hence: production of urea in hepatocytes regulated by AA level, rather than [NH3]

34
Q

What happens with fumarate after being synthesized in the urea cycle?

A

fumarate enters citrate cycle, used for gluconeogenesis
(already in postabsorptive phase)

35
Q

Where do Asp and Orn as substrates in the urea cycle come from?

A
  • ornithine synthesized from Glu/α-KG
    = anaplerotic reaction
  • Asp synthesized from OXA (from citrate cycle) by ASAT in mitochondria, then exp. into cytosol
36
Q

What happens in case of a [NH4+] so it cannot be all used for the urea cycle?

Reaction.

A

used by GLDH to aminate α-KG → Glu

α-KG + NADPH + NH4+ → Glu + NADP+ + H2O

NOTE: requires NAPDH; NADH formed in deamination reaction

37
Q

How is the urea cycle regulated?

A
  • allost. act. of CPS I by N-acetyl-Glu
    → presence of Glu, energy
  • enzyme induction during high protein diet, starvation
  • intermediate concentration
  • Arg: act. Nac-Glu synthetase
  • Orn: de novo synthesis (cf. own card)
38
Q

What is a hyperammonemia?

How is it generally treated?

A

= defect of urea cycle
→ GLDH uses α-KG for removal of NH3,
hence citrate cycle is depleted, low ATP level

treatment:

  • limited intake of protein, glucose (insulin)
  • inhibition of bact. NH3 release in colon (lactulose)
  • administration of AA binding chemicals:
    benzoate (Gly), phenylacetate (Glu)
  • replacing missing intermediates
39
Q

Distinguish btw hyperammonemia type I and II w/r/t

  • underlying enzyme defect
  • symptoms
  • treatment
A

type I = CPS I deficiency

  • ​symptoms: mental retardation
  • treatment: Arg supplementation to stimulate Nac-glu synthetase

type II = ornithine transcarbamoylase
most common form of hyperammonemia

  • symptoms: X-chromosal inheritance, mental retardation, orotic aciduria

orotic aciduria = carbamoyl not used for synth of citrulline, hence citrulline used in cytosol for synthesis of pyrimidine bases

40
Q

Which further enzyme defects/deficiencies are associated with the urea cycle?
Describe w/r/t

  • symptoms
  • treatment
A

arginosuccinate synthetase def.

  • symptoms: citrullinemia
  • treatment: Arg supplementation

arginosuccinate lyase def.

  • symptoms: arginosuccinate excretion
  • treatment: Arg supplementation

arginase def.

  • symptoms: high Arg level, abnormal CNS development
  • treatment: Arg-free diet
41
Q

Describe how the intestines contribute to the synthesis of Arg?

A

form citrulline to be transported to kidney for Arg synthesis

  1. 25% of urea synthesized in liver enters intestine, cleaved by urease of intestinal bacteria
    urea → NH4+ + HCO3-
  2. produce carbamoyl-P via CPS I, then used w/ ornithine to synthesize citrulline
42
Q

Which organ is responsible for formation of Arg?
Explain.

What are the functions of the synthesized Arg?

A

2-4g/d (∽ daily dietary intake) synth. in kidneys
citrulline from int. → urea cycle → Arg

⇒ then released into circulation for synthesis of
NO and polyamines in extrahep. tissues

⇒ Arg = only semi-essential AA

(bc in liver high arginase activity to enhance NH4+ excretion, Arg merely secreted into blood stream)

43
Q

Which enzyme is responsible for the synthesis of Gln?
Why is it important?

Reaction.

A

Gln synthetase
together with CPS I most imp. reaction of fix NH4+

Glu + ATP + NH4+ → Gln + ADP + Pi

⇒ Gln is 1 of the 2 transport forms of amino nitrogen in blood, acts as amino group donor

<u>NOTE:</u> reverse reaction cat. by glutaminase

44
Q

Which enzyme is responsible for the synthesis of Asn?

Reaction.

A

Asn synthetase

Gln + Asp + ATP → AMP + PPi + Glu + Asn

<u>NOTE:</u> synthesis of Asn is irreversible, can only be used for protein synthesis

45
Q

What are the 2 transport forms for amino nitrogen?

A

Gln + Ala ⇒ enter

  • glutamine cycle
  • alanine cycle
46
Q

Describe the release of the 2 transporter AAs Ala and Gln from muscle into the blood stream.

A
  • Ala = formed from pyruvate (glycolysis) by ALAT
  • Gln = formed from Glu by glutaminase
    (proteolysis in muscle → BCAAs → products = substrates of citrate cycle → α-KG transaminated to Glu)
47
Q

Describe the glutamine cycle (not in brain).

A
  1. Gln released from muscle due, adipose tissue and lung into blood stream
  2. absorbedy by liver, excess amount enters urea cycle
  3. remaining Gln + urea secreted into blood stream
  4. both taken up by kidney
    → urea excreted
    → Gln converted, used for gluconeogenesis, NH3 used to neutralize urine
48
Q

Describe the alanine cycle.

A
  1. Ala rel. from working muscle, intestine (food) into blood stream
  2. taken up by liver, glucose reformed
  3. glucose released again into blood stream

→ analogous to Cori cycle (lactate)

Biochemistry II (16 decks)

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