L40 41 Urea Flashcards
Overall AA catabolism
catbon skeleton metabolized to TCA intermediates and glucose
alpha amino group NH3 excreted in urine at NH4
-primary detoxed by liver via urea cycle
significance of protien degredation
body pool of AA
-amino acids derived from dietary protien: stimulate just enough insulin to prevent muscle breakdown
-breakdown of body protein- fasting state-muscle major source of aa for carbon for gluconeogenesis (broken down via ubiquitination and proteosomal degradation) high during low IG ratio
what does the liver process
location of MOST aa catabolism
EXCEPTION-BCAA (LIV) - these are only done in peripheral tissues
during fasting AA are the main source of carbon for the liver..then for the kidney
Three types of amino acids
glucogenic
-aa that enter the TCA cycle (w/out consuming OAA) and lead to a net INCREASE in OAA which can be used for gluconeogenesis
Ketogenic: AAs that form AcCoA or Acetoacetate (cannot form glucose because two acetyl coA carbons are lost as CO2 in subsequent reaction) no net gain of C
BOTH: several AAs (ty, ile, phe, trp can be used for either glucose or Ketone body synthesis) depending where they enter the TCA cycle
Muscle Breakdown during fasting. What is happening in the Muscle Liver and Kidney
liver will catabolize MOST for gng, lacks enzymes to break down BCAA (liv)
Muscle: BCAA carbons: cat for energy: TCA/ETC
- BCAA nitrogens released into circ on alanine and glutamine
- nBCAAs- released into circ intact (for liver)
liver: takes up nbcaa for gng/kg
- alanine from muscle used for glucose production
- amino nitrogens are siposed of as urea or glutamine
Kidney: takes up glutamine for nitrogen disposal and glucose synthesis (PROLONGED FAST)
draw path of branch chained and non branch chained AAs to disposal or recycle
include BCAA- Glutamate- alanine, glutamine, liver/kidney S9
ala and gln concentrations in circulation and where it is going
incorporation of amino groups from BCAA into alanine and glutamine in muscle results in disproportionately large release of ALA/GLN in circ.
C skeletons of these AA are used for gluconeogenesis, or in case of glutamine, provide nutrients to tohter tissues.
Transamination reaction of Nitrogen disposal
- remove alpha Amino from AA (deaminate)
- 12 different aminotransferase enzymes for the 20 AA
- named for the donor of the amine group
- only muscle has aminotransferase enzymes that can act of BCAA
- either direction
- depends on tissue
Transamination reaction components
Amino acid-NH3 donates NH3, the leftover carbon skeleton used for gluglose energy as ALPHA KETO ACID.
-combined with alphaketoglutarate : substrate for every transamination reaction, which becomes GLUTAMATE with NH3 attached, sent to urea cycle
Pyridoxal phosphate temporarily holds Alpha amino group as its being transferred from the AA to Alpha ketogluterate
-pyridoxal 5 phosphate (PLP) is active coenzyme form of Vit B6 (present at catalytic site of all amino transferase enzymes)
(also holds amino group for aspartate when its becoming OAA)
DRAW
BCAA Aminotransferases
in muscle transfers amino group from BCAA (liv) to a-ketogluterate
-products: glutamate and a-keto acid
-glutamate then gives nitrogen to alanine or glutamine
- -liver can then use ALANINE
- Kidney can then use glutamine
the a-keto acid then needs to have carboxyl group removed in breakdown
- BCketoacid dehydrogenase complex (BCKD)
- rate limiting enzyme in conversion of aketoacid into ketone bodies of TCA cycle
- DEFECTIVE IN maple syrup urine disease
MSUD
maple syrup urine disease
-inherited defect of BCKD
symptoms a few days after birth
elevated BCAA in blood stream due to alpha keto acid accumulation and inhibition of forward BCAA reaction
-BCAA isoleusine gives maple syrup odor to urine
ketoacidosis (accumulation of aketoacids of the BCAA)
encephalopathy (brain dysfuntion) from buldup of BCAA and aketoacids. Leucine is most abundant BCAA that acuumulates. Starts to cross BBB and metabolized to glutamine and glutamate
neonatal screening, some states a routine test for heel blood of high leucine levels
infants must be fed synthetic formula with limited amounts of BCAA, and lifelong dietary mods to avoid BCAA
glucose alanine cycle
glutamate can donate N to pyruvate creating alanine and a-kg via muscle ALT (alanine aminotransferase), alanine goes into circulation, and used via liver ALT to generate BACK to pyruvate (a-keto acid) for gluconeogenesis in liver
GLUCOSE ALANINE CYCLE
alanine and glutamine in muslce
bcaa breakdown leades to glutamate which can be changed to glutamine or alanine. both non toxic amino acid carriers
alanine: in muscle, formed by the amination of pyruvate (by glutamate), then it is sent to liver and deaminated in the liver for glucose synthesis for gluconeogenesis (glucose alanine cycle) ONLY OCCURS IN FASTING STATE
glutamine: both muscle and liver- glutamate canundergo additional amination to form glutamine. ATP dependant and catalized by GLUTAMINE SYTHASE
- this is the mop up role that was not metabolized by urea cycle
breaking down non branch chain amino acids in liver
nBCAA (diet or muscle) taken up by liver and deaminated by 1 of 12 different aminotransferases
in liver, the nBCAA transfer aa to a-kg creating GLUTAMATE and a-ketoacid.
-glutamate will serve as N carrier for urea cycle OR become glutamine
glutamate in Urea cycle has two possible ways to donate NH3, urea is one way to dispose nitrogen
- oxidative deamination: produces free NH3
- GLUTAMATE DEHYDROGENASE uses NAD to oxidize the carbone skeleton of glutamate, making a-ketogluterate and free NH3 (can be protonated to NH4)
- NH4 will be in first step of urea cycle: synthesis of cabomoyl phosphate via the RL enzyme CARBAMOYL PHOSPHATE SYNTETASE I (CPSI) (2 ATP reguired) (in mito) - second transamination reaction creating aspartate
- aspartate transaminase ransferes the amino group from glutamate to OAA forming aspartate
- aspartate reacts with citrilline in the urea cycle to bring in a second nitrogen and creates arginosuccinate
