---
title: Acetyl-CoA & ACOT:s & ACS:s
disqus: hackmd
---

:::success
> Documentation [name=MrDr.Staffan]
###### tags: `page`, `acetyl-CoA`
:::

:::info
### Table of Contents
[TOC]
:::
[Top](#Table-of-Contents)

**Why this page?**
Acetyl-CoA

---

Compartmentalised acyl-CoA metabolism and roles in chromatin regulation
https://www.sciencedirect.com/science/article/pii/S2212877820300077

---

The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins


https://www.sciencedirect.com/science/article/pii/S2211124715014540

Elevating acetyl-CoA levels reduces aspects of brain aging
https://elifesciences.org/articles/47866

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain
https://www.frontiersin.org/articles/10.3389/fncel.2018.00169/full

# Acetate Revisited

[Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics and Oncogenesis—Part 1: Acetyl-CoA, Acetogenesis and Acyl-CoA Short-Chain Synthetases](https://www.frontiersin.org/articles/10.3389/fphys.2020.580167/full)

[Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis – Part 2: Acetate and ACSS2 in Health and Disease](https://www.frontiersin.org/articles/10.3389/fphys.2020.580171/full)

# Big review.
2015 Pietrocola... Kroemer - Acetyl Coenzyme A: A Central Metabolite and Second Messenger
https://www.sciencedirect.com/science/article/pii/S1550413115002260
Figure 1. Mitochondrial and Nucleo-Cytosolic Bioenergetic Metabolism of Acetyl-CoA in Mammalian Cells

Figure 2. Compartmentalization of Acetyl-CoA Metabolism

Figure 3. Impact of the Acetyl-CoA/CoA Ratio on Global Cellular Functions

Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger.

---

Acetyl-CoA is indeed the actual molecule through which glycolytic pyruvate enters the tricarboxylic acid (TCA) cycle

Key precursor of lipid synthesis & Beta-oxidation

Sole donor of the acetyl groups for acetylation (Choudhary et al., 2014)

Regulation of Autophagy by Cytosolic Acetyl-Coenzyme A

# Acetyltransferases

[See epigenetics HATs // KATs](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FFTG3zDLIRjOQtrWE2DD6gg#Histone-acetyltransferase-HATs)

protein acetyltransferase complex GO:0031248

Enzymes catalyzing the transfer of an acetyl group, usually from acetyl coenzyme A, to another compound. EC 2.3.1.

HATs CAT ChAT SNAT NAT NAT

(HATs) Histone acetyltransferases incl. CBP histone acetyltransferase (domain on CREB binding protein)
[KATs] Lysine acteyltransferase
(ChAT) Choline acetyltransferase
(CAT) Chloramphenicol acetyltransferase
(SNATs) Serotonin N-acetyltransferase (SNATs)
NatA Acetyltransferase
NatB acetyltransferase

(HATs) Histone acetyltransferases incl. CBP histone acetyltransferase (domain on CREB binding protein) https://sci-hub.se/10.1016/B978-0-12-805388-1.00020-1
[KATs] Lysine acteyltransferase
(ChAT) Choline acetyltransferase
(CAT) Chloramphenicol acetyltransferase
(SNATs) Serotonin N-acetyltransferase (SNATs)
NatA Acetyltransferase
NatB acetyltransferase

# De-acetyltransferase

[See epigenetics HDACs](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FFTG3zDLIRjOQtrWE2DD6gg#Histone-deacetylase-HDACs)

HDACs (histone-) aka KDACs (lysine-)

hdac1 hdac2 hdac3 hdac4 hdac5 hdac6 hdac7 hdac8 hdac9 hdac10

# Co-enzyme A
Fritz Lipmann in 1946
diphospho 3′-phosphoadenosine

CoA

## Acetyl-CoA
[Top](#Table-of-Contents)

acetyl coenzyme A
TCA
Synthesis of alot of things

acetyl moiety (CH3CO) linked to coenzyme A (CoA) a derivative of vitamin B5 and cysteine, through a thioester bond.

AcetylCoA functions in the **allosteric regulation** of proteins as well as the stimulation or inhibition of signaling pathways coordinating several metabolic pathways [5]. Phosphorylation and dephosphorylation of proteins are frequent regulatory mechanisms that can be influenced by acetylCoA’s effect on some protein kinases

AcetylCoA is sequestered in the cell and in subcellular organelles because it cannot be transported across membranes. **If it is at too high a concentration at one location, carnitine can facilitate transportation of the activated acetate from that location**. The conversion of acetylCoA to acetylcarnitine will immediately reduce the acetylCoA concentration and will also release free coenzyme A, which may be present in limiting amounts and required to meet immediate needs.

Carboxylic acids in metabolism
Numerous metabolites in amino acid metabolism and carbohydrate metabolism are carboxylic acids. The role of acylcarnitines in amino acid and carbohydrate metabolism often receives less attention than their role in fatty acid oxidation, but is of no less importance.

Insulin resistance is closely related to carnitine metabolism [6]

L. L. Jones, D. A. McDonald, and P. R. Borum, Acylcarnitines: Role in Brain,
Prog Lipid Res, 49 (2010), 61–75.

Acylcarnitines: Role in brain
https://www.sciencedirect.com/science/article/pii/S0163782709000435

**Octanoic acid // Caprylic acid // Octanoate (HMDB0000482)**
While glucose is thought to be the primary energy source for
the adult brain under normal conditions, recently it was shown
that fatty acids can be used by the brain as well. Almost 20% of
the total oxidative energy produced in brain was from the oxidation of 13C-octanoate in adult male Sprague–Dawley rats [https://doi.org/10.1523/JNEUROSCI.23-13-05928.2003]

"We hypothesized that fatty acid oxidation in brain could contribute significantly to overall energy usage. Previous studies of fat oxidation in brain have been limited to acetate, the simplest of fats (Badar-Goffer et al., 1990; Cerdan et al., 1990; Hassel and Sonnewald, 1995; Sonnewald et al., 1996; Lebon et al., 2002); however, acetate is not a primary physiological fuel for brain (Vannucci and Hawkins, 1983; Edmond, 1992). Conversely, octanoate is a medium-chain **fatty acid that composes up to 13% of the normal free fatty acid pool in humans** (Mamunes et al., 1974), readily crosses the blood–brain barrier (Oldendorf, 1971, 1973), and is an important component of medium-chain triglycerides used in various clinical settings (Sulkers et al., 1989; Eckel et al., 1992; Rouis et al., 1997; Gillingham et al., 1999)"

Acetylation can occur as a co-translational event. In this setting, Nα acetyltransferases (NATs) transfer an acetyl group from acetyl-CoA to the α-amino group of the N-terminal residue of the protein (which generally is serine, alanine, glycine, threonine, valine, or cysteine), once the initiator methionine has been removed by methionine aminopeptidases

N-terminal acetylation affects the vast majority of human proteins, determining their stability, localization, and function (Hollebeke et al., 2012).

* In response to a series of physiological or pathological conditions, the abundance and/or distribution of acetyl-CoA in distinct subcellular and/or pericellular compartments changes considerably.

* Thus, acetyl-CoA can act as a second messenger that relays signals from the extracellular to the intracellular milieu.

* This may contribute to the elevated variability in lysine acetylation patterns encountered in organs and subcellular fractions in distinct functional states (Lundby et al., 2012)

# Acetyl CoA synthesis

## AcetylCoA synthases

[See Acetyl CoA synthase in Lipid metabolism III](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FLviQI1LDRae6qatO08KKLQ#acyl-CoA-synthetases-ACSs--Acetyl-CoA-ligases)

**Miochondria**
Fatty acids
Pyruvate
Branched-chain amino acid (BCAA via BCKDH)

**Cytosol**
Acetate
Citrate

## Changing Acetyl-CoA Levels In Vivo
Mice deprived of food (but with access to water ad libitum) for 24 hr exhibit a significant reduction in total acetyl-CoA levels in several organs, including the heart and muscles, corresponding to a decrease in protein acetylation levels (Mariño et al., 2014 - https://www.sciencedirect.com/science/article/pii/S109727651400077X)

Exogenous supply of acetyl-coenzyme A prevents starvation-induced autophagy

However, the same experimental conditions have no major effects on acetyl-CoA concentrations in the brain (Mariño et al., 2014) and actually increase hepatic acetyl-CoA and protein acetylation levels (Chow et al., 2014)

In contrast, brain tissue, in which autophagy induction is not observed after fasting (Mizushima et al., 2004), presented no alterations in AcCoA levels or protein acetylation even after prolonged (48 hr) starvation

Mice were starved for 24 h, and hearts (E), muscles (F) and brains (G) were fixed and processed for immunofluorescence detection of acetyl-lysine epitopes
**Mariño et al., 2014**

# ER & Nuclear CoA
 

## SLC33A1 / AT-1
Transporter of acetyl-CoA. Expressed in all tisues and cells tested. In various cellular studies, Huppke et al. (2012) found that the SLC33A1 protein showed a perinuclear cytoplasmic distribution and localized to the Golgi apparatus.

Acetylation of ER cargo proteins is ensured by three essential elements: AT‐1, ATase1, and ATase2

## Mitochondrial Acetyl-CoA

SLC25A42 - Mitochondrial coenzyme A transporter
BarresMm_Astro.Hs_Neg

OldHLow_striatum_neurons?

LinnarssonMm_var

# Consequences of Acetylation


Acetylation of non-histone proteins modulates cellular signalling at multiple levels
https://www.sciencedirect.com/science/article/pii/S1357272508003476?via%3Dihub#aep-section-id22

SUMOylation and deSUMOylation at a glance
https://jcs.biologists.org/content/122/23/4249

## Proteins (General)

## Histones

## Lipids in membranes

cell membrane stability by acetylation of phospholipids and amphiphilic actions

# ACOTs
[Also See Acot11](https://hackmd.io/@sholmqvist/BJN5dmhLu/%2FnvDL08euS2WxOF5dt1rOzA)

[See Sharma 2015 Acot:s proteomics](https://docs.google.com/spreadsheets/d/1w32HIRZfz-5ZrBswyEgS9Se63jPfDCsdZKbP7Gh8JlY/edit#gid=442921000)

[See Slides Astrocyte TCA](https://docs.google.com/presentation/d/1OBWe0RZk7GlKqi6yrUXaou-iYRY9BSwG5OhjTSUT1u0/edit#slide=id.g12fd9a739a2_1_27)

[See Slides Acot Notes](https://docs.google.com/presentation/d/14CaYS1_arK7MZh09CnVHSebq9kEgbrtQc1kzyIN0qDo/edit#slide=id.ge09430e5eb_0_96)

ACOT- family of enzymes suggested role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids.

[2012. The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism](https://www.sciencedirect.com/science/article/pii/S0925443912000749?via%3Dihub#f0005)

The importance of peroxisomes in lipid metabolism is now well established and peroxisomes contain approximately 60 enzymes involved in these lipid metabolic pathways. Several acyl-CoA thioesterase enzymes (ACOTs) have been identified in peroxisomes that catalyze the hydrolysis of acyl-CoAs (short-, medium-, long- and very long-chain), bile acid-CoAs, and methyl branched-CoAs, to the free fatty acid and coenzyme A.

---

ACOT11 has a preference for MCFAs C12 and LCFA C18.
Induced by cold and repressed by warmth.

[To me this suggest a shift in CoA from long to short Substrates.
Which should mean fuel.]

if acot11 has a preference for c14-coA
This means that when it is cold and acot11 is up, then less c14 is associated with CoA. If CoA association Is needed for b-ox.Then cold reduce c14 available for fuel and more can associate with protein - thereby targeting the proteins for the membrane. This increase membrane fluidity.]
[I often reason that cold removes SFA from membranes to stabilizes fluidity
Cold therefore shift membranes from having SFA phospholipids toward protein content. And this increase /stabilizes membrane fluidity.
Does any (SFA) phospholipase become active. In cold? Look this up!]

20230303.

[See Phospholipase](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2FHi_KrVDMS72extkwqJfUJw#Phospholipases)


[2019. Selectivity of phospholipid hydrolysis by phospholipase A2 enzymes in activated cells leading to polyunsaturated fatty acid mobilization](https://doi.org/10.1016/j.bbalip.2018.07.002)
PLA1A
LIPH

There are very many phospholipase.

### ACOT - Acyl-CoA Thioesterases

[# Paper idea. "Brain astrocytes sense low temperature and lower palmitoyl-metabolism"] // regulate lipid retention and metabolism, KO should induce increased lipid (palmitoyl) flux. Compare to the effect of Acot7 in neurons

[Also see peroxisomes - Acots](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F8vV6VyEFSsyHiWH_OZ1_hw#Acots)

Acot1 Acot2 Acot3 Acot4 acot5 acot6 acot7 acot8 acot9 acot10 acot11 acot12 acot13

Review
2012 - The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism☆


ACOT1 Astro
ACOT2 General
ACOT5&6 in Ependymal

ACOT7 Neurons + var
ACOT8 Oligodendrocyte2
ACOT11 Astro (BAT, Obesity)

Neuron1 (Acot, 7,8,9,10, -, 12,13

[#Since Neurons1 have more Type2 acots than astro. And Astro have same as BAT, is that ACOT11 constituitively active version?]





**Acyl-CoA Thioesterases**
group of enzymes that hydrolyze Coenzyme A (CoA) esters, such as acyl-CoAs, bile CoAs,
and CoA esters of prostaglandins, to the corresponding free acid and CoA.

Potentially regulated all CoA dependent systems.
Eg.
Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.

Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[10] hexokinase IV,[11] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[12] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[13][14][15] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[16] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[17] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.

THEM4 Thioesterase Superfamily Member 4
THEM6
PPT1 Palmitoyl-Protein Thioesterase 1

# Abhydrolase Domain Containing ABHDs
https://www.frontiersin.org/articles/10.3389/fimmu.2020.01388/

This domain is present in Type I ACOTs 1-6
**ABHD2** Human ABHD2 was highly expressed in sperm and functioned as a lipid hydrolase through the activation of steroid hormone progesterone (https://doi.org/10.1126/science.aad6887)
**ABHD4** Mouse ABHD4 regulated the metabolism of multiple N-acyl phospholipids in the central nervous system (https://doi.org/10.1021/acs.biochem.5b00207)

human **ABHD5**, known as Chanarin-Dorfman syndrome protein, acted as a ligand-regulated lipase activator through the interaction with Perilipin to modulate lipolysis (5).

**ABHD15** is a directly target gene of peroxisome proliferator-activated receptor gamma and blocking ABHD15 expression resulted in apoptosis of 3T3-L1 cells (7

++Barres Mm++
abhd1 (Astro)
Abhd2 (OPC + Endo)
**abhd3** (**astro**) also linnarsson
abhd4 (oligod + astro)
abhd5 var
abhd6 var
abhd7 Ephx4
abhd8
abhd9
abhd10 var
abhd11 var
abhd12 (abdh12b Hs Oligo)
abhd13 var
abhd14 var
abhd15 m.g.
Abhd17a // Fam108a
Abhd17b // Fam108b
Abhd17c // Fam108c
Abhd18



# ACATs
ACAT1 ACAT2 = (Acetyl-CoA Acetyltransferase)
are not
SOAT1 ("ACAT1") SOAT2 ("ACAT2") = Sterol Acetyltransferase

Human ACAT3 does not excist in Mouse
Mouse Acat3 is human ACAT2

[Also see Lipids IX Vesicles](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FKQmhUjePRYmuCEfi9eys_w)
[Also see Lipids VII Cell types - Cholesterol](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FUvNTWpCvR3W68aoFEHwRiQ#Cholesterol)

ACAT1
ACAT2
Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and -

LCAT Lecithin-Cholesterol Acyltransferase

BAAT Bile Acid-CoA:Amino Acid N-Acyltransferase

# ACSL Acyl-CoA synthese Long, medium, short (opposite of ACOTs.)

[#Question]
E.g. In acot7 KOs is any of these ACSLs upregulate?
==Indicative of a shift in from fuel to lipid synthesis???==

Acsl1 Oligo
Acsl3 Astro + oligo
Acsl4 Neuron1
Acsl5 Neuron1
Acsl6 Astrocytes

Acot8 Oligo2
Acot11 Astro
Acot7 Neuron



Acsl1 Acsl2 Acsl3 Acsl4 Acsl5 Acsl6


# Zdhhc:s
Probable Palmitoyltransferases

[Also see Palmitoylation](https://hackmd.io/@sholmqvist/BJpKurTBB/%2FArIdX3sNQNmpB7okZDFLBQ#palmitoylation-C160)

Zdhhc1 Zdhhc2 Zdhhc3 Zdhhc4 Zdhhc5 Zdhhc6 Zdhhc7 Zdhhc8 Zdhhc9 Zdhhc11 Zdhhc12 Zdhhc13 Zdhhc14 Zdhhc15 Zdhhc16 Zdhhc17 Zdhhc18 Zdhhc19 Zdhhc20 Zdhhc21 Zdhhc22 Zdhhc23 Zdhhc24 Zdhhc25


# Unrelated ACADs
[See ACADs in b-ox](https://hackmd.io/@sholmqvist/BJpKurTBB/%2F3aYvl2nvTye4CSAsWO_P8g#Beta-oxidation)