Enzymes and regulation

Last updated on March 11, 2020 at 17:39

General rules about regulation:

  • Hormones always regulate stuff indirectly
  • Hormones almost always regulate stuff covalently
  • Kinases or phosphatases almost always regulate stuff covalently
  • Something that’s not a protein can never regulate anything covalently directly

The ones I think are most important are bolded.

Most of them are taken from Lehninger 6th edition. The “Page” column shows which page from the book has been used as a source.

Acetyl-CoA carboxylase

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme of fatty acid synthesis. It converts acetyl-CoA to malonyl-CoA with the help of the cofactors biotin, ATP and CO2. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page 
Glucose Transcriptional Indirect Through PP2A and ChREBP 609
Xylulose 5-phosphate Transcriptional Indirect Through PP2A and ChREBP 609
PP2A Transcriptional and covalent Indirect and direct Through ChREBP and directly 609, 679
Insulin Covalent Indirect Through PP2A 679
Citrate Allosteric Direct   842
Cholesterol Transcriptional Indirect Through LXR 871
Glucagon, epinephrine Covalent Indirect Through PKA 679
AMP Covalent Indirect Through AMPK 679
Palmitoyl-CoA Allosteric Direct   842

Carbamoyl phosphate synthetase I

Carbamoyl phosphate synthetase I (CPS I) is the rate-limiting enzyme of urea synthesis. It should not be confused with carbamoyl phosphate synthetase II, which is the rate-limiting step of de novo pyrimidine synthesis. It is located in the mitochondria.

N-acetylglutamate is a breakdown product of amino acids. When more amino acids are broken down the urea cycle is sped up (by the increased amount of N-acetylglutamate) to prevent ammonia, another breakdown product of amino acids, from accumulating.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
N-acetylglutamate Allosteric Direct   708
Acetyl-CoA Allosteric Indirect Through N-acetylglutamate 708
Glutamate Allosteric Indirect Through N-acetylglutamate 708
Arginine Allosteric Indirect Through N-acetylglutamate 709

Carnitine acyl-transferase 1

Carnitine acyl-transferase 1 (CAT 1) is the main enzyme in the carnitine-dependent shuttle. Fatty acids are activated in the cytosol (on the outer mitochondrial membrane), but they must be transported into the mitochondrial matrix to be oxidized. Short and medium-length fatty acids can freely diffuse across the mitochondrial membrane, but long fatty acids (like palmitoyl-CoA) cannot. Palmitoyl-CoA is instead converted into palmitoylcarnitine by CAT1, which is shuttled across the mitochondrial membrane by a transport protein. When inside the mitochondrial matrix, palmitoylcarnitine is converted back into palmitoyl-CoA.

It is the rate-limiting step of beta oxidation. Malonyl-CoA is a product of fatty acid synthesis. Because malonyl-CoA inhibits CAT1, fatty acid synthesis inhibits beta oxidation.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Malonyl-CoA Allosteric Direct Malonyl-CoA is produced by ACC  

Fructose 1,6-bisphosphatase (FBPase-1)

Fructose 1,6-bisphosphatase (FBPse-1) is the rate-limiting enzyme in gluconeogenesis. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucagon Allosteric Indirect Through F26BP 606
AMP Allosteric Direct   605
Insulin Allosteric Indirect Through F26BP 606
F26BP Allosteric Direct   605

Glucokinase (hexokinase IV)

Glucokinase is involved in glycolysis. It is located in the liver and beta-cells of the pancreas. Because glucokinase has a low affinity for glucose the liver will only store glucose as glycogen when the blood glucose level is high.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Transcription Indirect   952
Glucose Transport out of the nucleus Indirect Through a regulatory protein 603
Low [ATP] Transcription Indirect   603
Fructose 6-phosphate Transport into the nucleus Indirect Through a regulatory protein 603

Glycogen phosphorylase

Glycogen phosphorylase is the rate-limiting step of glycogenolysis. It requires PLP as a cofactor.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucagon Covalent Indirect In liver, through PKA 621
Epinephrine Covalent Indirect In muscle and liver, through PKA 621
[Ca2+] ↑ Covalent Indirect In muscle. Ca2+ is the signal for muscle contraction 621
[AMP] ↑ Allosteric Direct In muscle 621
Insulin Covalent Indirect   621
PP1 Covalent Direct and indirect Indirect via phosphorylase kinase. They often ask about this! 621
Glucose Allosteric Direct   622

Glycogen synthase

Glycogen synthase is the rate-limiting enzyme in glycogenesis (glycogen synthesis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
G6P Covalent and allosteric Indirect (covalent) and direct (allosteric) Covalent: By making it easier for PP1 to dephosphorylate 623 (covalent), ass. prof. Lengyel (allosteric)
PP1 Covalent Direct   623
Insulin Covalent Indirect by two ways Through PP1 and GSK3 623
Glucose Covalent Indirect By making it easier for PP1 to dephosphorylate 623
Casein kinase II Covalent Direct   623
Glucagon, epinephrine Covalent Indirect Through PKA 623
GSK3 Covalent Direct   623
AMPK Covalent Direct   Figure 23-40

Hexokinase I-III (not glucokinase)

Hexokinase is the rate-limiting step of glycolysis in all tissues except the liver and beta-cells. Because it has high affinity for glucose, all tissues that use hexokinase will utilize glucose even when the blood glucose level is normal.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Transcription Indirect    
Glucose Allosteric Direct    548, 591
Glucose 6-phosphate Allosteric Direct   602, 762

HMG-CoA reductase

HMG-CoA reductase (HMG-CoAR) is the rate-limiting enzyme of cholesterol synthesis. It is located in the membrane of ER.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Insulin Covalent Indirect Through PP2A 870
Low intracellular cholesterol Transcriptional Indirect Through SREBP and SCAP 871
Glucagon Covalent Indirect Through PKA 870
AMP Covalent Indirect Through AMPK 870
High intracellular cholesterol Proteolysis Indirect Through oxysterol with Insig 871

HMG-CoA synthase (mitochondrial)

Mitochondrial HMG-CoA synthase is the rate-limiting enzyme of ketone body synthesis. Cytosolic HMG-CoA synthase is an enzyme in the cholesterol synthesis, but it is not the rate-limiting one and is therefore not very important.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Acetyl-CoA Allosteric Direct   Biochem 1 lecture
Succinyl-CoA Covalent Direct By succinylation Biochem 1 lecture

PEP carboxykinase

PEP carboxykinase is an irreversible enzyme in the gluconeogenesis. It is located in the cytosol.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Glucocorticoids (liver) Transcriptional ? Only in liver  
Thiazolidinediones (in adipose tissue) Transcriptional ? Only in adipose tissue  
Glucocorticoids (adipose tissue) Transcriptional ? Only in adipose tissue  

Phosphofructokinase-1 (PFK1)

Phosphofructokinase-1 (PFK1) is the rate-limiting enzyme in glycolysis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
F26BP Allosteric Direct   605
Insulin Allosteric and transcriptional Indirect Through F26BP  
AMP, ADP Allosteric Direct   762
ATP Allosteric Direct   762
Glucagon, epinephrine Allosteric Indirect Through F26BP  
Citrate Allosteric Direct   762

Pyruvate carboxylase

Pyruvate carboxylase is an irreversible enzyme in the gluconeogenesis. It is located in the mitochondria and requires biotin and ATP.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
Acetyl-CoA Allosteric Direct   608

Pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex (PDH) is an enzyme which connects the glycolysis to the TCA cycle by converting pyruvate to acetyl-CoA. It is located in the mitochondria. It requires 5 cofactors; TPP, lipoate, CoA, FAD and NAD.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
AMP Covalent Indirect Through pyruvate dehydrogenase kinase 654
CoA Allosteric Direct   654
NAD+ Allosteric Direct   654
Ca2+ Allosteric Direct   654
ATP Covalent Indirect Through pyruvate dehydrogenase kinase 654
Acetyl-CoA Allosteric Direct   654
NADH Allosteric Direct   654
Fatty acids Allosteric Direct   654

Pyruvate kinase

Pyruvate kinase is an irreversible enzyme in the glycolysis.

Substance Allosteric/covalent Direct/indirect Activated/inactivated Comments Page
F16BP Allosteric Direct   607
Insulin Covalent and transcriptional Indirect Covalent: Through PP1, only in liverTranscriptional: Through ChREBP 607
ADP Allosteric Direct   762
ATP Allosteric Direct   762
Long-chain fatty acid Allosteric Direct   607
Acetyl-CoA Allosteric Direct   607
Alanine Allosteric Direct   607
Glucagon Covalent Indirect Through PKA, only in liver 607

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